62 results on '"Hausenloy, DJ"'
Search Results
2. Targeting DJ-1 for cardioprotection
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Hernandez Resendiz, S, primary, Lu, S, additional, Prakash, A, additional, Crespo-Avilan, GE, additional, and Hausenloy, DJ, additional
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- 2022
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3. P645T2-mapping cardiac MRI for in vivo quantification of myocardial area-at-risk
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Dongworth, RK, Campbell-Washburn, AE, Roberts, T, Yellon, DM, Lythgoe, MF, and Hausenloy, DJ
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- 2014
- Full Text
- View/download PDF
4. P445The differential effects of Sirtuin-3 in cardio-protection
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Hall, A R, Dongworth, RK, Kumar, S, Burke, N, Yellon, DM, and Hausenloy, DJ
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- 2014
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5. P166Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
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- 2014
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6. P143Targeting the mitochondrial fission proteins, MiD49 and MiD51, as a therapeutic strategy for cardioprotection
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Samangouei, P, Elder, JM, Burke, N, Hall, A, and Hausenloy, DJ
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- 2014
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7. Targeting DJ-1 for cardioprotection.
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Resendiz, S Hernandez, Lu, S, Prakash, A, Crespo-Avilan, GE, and Hausenloy, DJ
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MYOCARDIAL reperfusion ,MYOCARDIAL infarction ,AMINO acid sequence ,SYSTOLIC blood pressure ,REPERFUSION injury - Abstract
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Medical Research Council (NMRC) Background Additional protection beyond timely reperfusion is still needed as more patients who have survived an acute myocardial infarction (AMI) developed heart failure (HF)1. DJ-1 was recently reported as a cytoprotective protein that preserves mitochondrial complex I activity and subsequently inhibits mitochondrial reactive species (ROS) production2. DJ-1 downregulation dramatically increases the susceptibility to cell death after myocardial infarction in mice. A substantial reduction in total DJ-1 protein levels in left ventricular tissue has been identified in patients at the end-stage of human HF3, suggesting that DJ-1 protects the myocardium against AMI cell death and is essential in the remodelling process post-infarct. Purpose: The translation of cardioprotection to clinical practice has been difficult, and it remains a challenge between the bench and the bedside. Nanotechnology has shown significant improvements in the settings of AMI. Given the protective effect observed with DJ-1, we designed ND-13, a new cell-permeable 13- fragment of the DJ-1 amino acid sequence. Then, we loaded it into nanoparticles (ND-13NPs) to achieve cardioprotective outcomes against IRI. Methods: We tested the efficacy and efficiency of our new ND-13NPs to reduce infarct size in the ex vivo heart perfused IRI model and the in vivo AMI-murine model. Results: Naked ND-13 (20µM) continuously perfused for the first 15 minutes of reperfusion significantly improved LV pressure and systolic function. Afterwards, we tested 60 mg/Kg of the naked peptide injected 5 minutes before reperfusion in the in vivo model. ND-13 reduced 35% of the infarct size (non-treated, 49 ± 6.4% vs. treated, 32 ± 5 %). Fluorescently loaded ND-13NPs were intravenously injected into infarcted mice to assess their distribution in cardiac tissue. The ND-13NPs were abundantly detected in the infarct border and minimally detected in the remote myocardium. 20mg/Kg of ND-13 loaded into NPs reduced 45% the infarct size compared with 60mg/Kg and 20mg/Kg of naked ND-13 (27 ± 6% vs. 32 ± 5% and 44 ± 8%, respectively). We demonstrated that NPs improved the delivery and efficacy of ND-13 in the ischemic heart following AMI. We observed a robust antioxidative effect when the infarcted heart was treated with ND-13NPs (90 ± 1.5% vs 39 ± 9%, respectively). The activation of the myocardial reperfusion injury salvage kinase (RISK) and the survivor activating factor enhancement (SAFE) pathway at reperfusion protects the mitochondria against IRI. Therefore, we addressed whether ND-13NPs impact mitochondrial function. Can ND-13 protect beyond a cardioprotective pathway, or has the threshold of protection already been achieved by activating a direct effect on mitochondria? Conclusion: Intravenously injected ND-13NPs selectively accumulated in the infarct area and protects the myocardium from IRI via the ROS-mitochondria effect. This new drug may potentially bridge the gaps between basic and clinical research. [ABSTRACT FROM AUTHOR]
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- 2022
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8. P143 Targeting the mitochondrial fission proteins, MiD49 and MiD51, as a therapeutic strategy for cardioprotection.
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Samangouei, P, Elder, JM, Burke, N, Hall, A, and Hausenloy, DJ
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TARGETED drug delivery ,MITOCHONDRIAL dynamics ,PROTEINS ,CARDIOVASCULAR system ,HEART disease related mortality ,REPERFUSION injury - Abstract
Background: Ischaemic heart disease is the major cause of morbidity and mortality worldwide. Novel therapeutic strategies are essential to protect the heart from acute ischaemia-reperfusion injury (IRI). It has been reported that inhibiting mitochondrial fission, protects the heart against cardiomyocyte death during acute IRI. We investigated the mitochondrial fission proteins, MiD49 and MiD51, as novel targets for cardioprotection,Methods and Results: Genetic ablation of both MiD49 and MiD51 in HL-1 cardiac cells (a murine atrial-derived cell line), using shRNAs had the following effects: (1) A significant increase in the proportion of cells expressing predominantly elongated mitochondria (81.5±2.9% MiD49+MiD51 knockdown vs. 49.4±4.9% vector control: n=120 cells/group; P<0.05); (2) It led to a delay in time taken to induce mitochondrial permeability transition pore (MPTP) opening (485±61 seconds MiD49+MiD51 knockdown vs. 233±20 seconds vector control: n=120 cells/group; P<0.05); (3) Cell death following simulated IRI was reduced (27.9±3.0% MiD49+MiD51 knockdown vs. 56.7±2.4% vector control: n=300 cells/group; P<0.05). Interestingly, the individual knockdown of either MiD49 or MiD51 alone had no effect on these parameters. Unexpectedly, the over-expression of either MiD49 or MiD51 had similar beneficial effects: (1) The formation of abnormally elongated (hyperfused) mitochondria with a peri-nuclear distribution; (2) It delayed the induction of MPTP opening (339±23 seconds MiD49 over-expression, 336±19 seconds MiD51 over-expression vs. 208±16 seconds vector control: n=120 cells/group; P<0.05); (3) It reduced cell death following simulated IRI (21.5±3.7% MiD49 over-expression, 20.0±3.7% MiD51 over-expression vs. 52.0±4.6% vector control: n=300; P<0.05). The explanation for this apparent beneficial effect with MiD49 or MiD51 over-expression, may be due to Drp1 sequestration to mitochondria, leading to unopposed abnormal mitochondrial elongation (hyperfusion).Conclusions: Here we show that combined knockdown of the newly discovered mitochondrial fission proteins, MiD49 and MiD51, induced mitochondrial elongation, delayed MPTP opening, and protected cells against simulated acute IRI, implicating MiD49 and MiD51 as novel targets for cardioprotection. Unexpectedly, the over-expression of these fission proteins induced a state of abnormal hyperfusion, delayed MPTP opening, and protected cells against simulated acute IRI. [ABSTRACT FROM AUTHOR]
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- 2014
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9. P445 The differential effects of Sirtuin-3 in cardio-protection.
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Hall, A R, Dongworth, RK, Kumar, S, Burke, N, Yellon, DM, and Hausenloy, DJ
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CELL lines ,PHOSPHORYLATION ,LABORATORY mice ,GENETIC mutation ,HEART physiology ,REPERFUSION injury - Abstract
Background: A mitochondrial specific deacetylase, Sirtuin-3 has been reported to regulate oxidative phosphorylation, the activity of Cyclophilin D (a key component of the mitochondrial permeability transition pore, MPTP), and the ROS scavenger MnSOD. We hypothesised that Sirtuin-3 could be a potential therapeutic target for cardio-protection based its ability to prevent MPTP formation and inhibit ROS generation.Methods and Results: In HL-1 cells (a murine cardiac cell line), over-expression of Sirtuin-3 reduced cell death following simulated ischemia-reperfusion injury (assessed by propidium iodide staining). Futhermore, Sirtuin-3 over-expression reduced MPTP formation (assessed by ROS-induced mitochondrial depolarization), and induced mitochondrial fusion (assessed by 3 blinded investigators and the PEG fusion assay). The catalytically inactive mutant form of Sirtuin-3 failed to mediate any of these beneficial effects. To investigate the role of endogenous Sirtuin-3 in the adult heart, Sirtuin-3 (whole body) KO mice and WT littermates were subjected to in vivo cardiac ischemia (30 min) followed by 24 hrs reperfusion. myocardial infarct (MI) size was determined as a percentage of area at risk. Interestingly, no differences in MI size were observed between WT and KO mice under fed conditions. However, overnight fasting (to induce Sirtuin-3 expression and activity) resulted in a smaller MI size in the Sirtuin-3 KO when compared to WT mice.Conclusions: We report that the role of Sirtuin-3 in cardio-protection differs between the HL-1 cardiac cell line and the adult heart. In the HL-1 cell, Sirtuin-3 over-expression had beneficial effects against acute IRI, suggesting that activating Sirtuin-3 in this cell-line may be cardio-protective. In contrast, fasted mice deficient in Sirtuin-3 had smaller MI following IRI, suggesting that inhibiting Sirtuin-3 in the fasted adult heart may be cardio-protective. This finding may have clinical implications in patients who are fasted before surgery. [ABSTRACT FROM AUTHOR]
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- 2014
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10. P166 Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1.
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
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RNA ,REPERFUSION injury ,HEART failure ,RIBONUCLEASES ,MORTALITY ,MYOCARDIAL infarction - Abstract
Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant. Extracellular RNA (eRNA), exposed after cell damage, serves as cofactor for coagulation proteases and cytokines thereby promoting their procoagulant and proinflammatory functions in vivo. Following myocardial ischemia/reperfusion (I/R) in mice or I/R induced in the isolated Langendorff heart, increased eRNA levels were found together with cell injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced tumor-necrosis-factor-a (TNF-α) liberation by activation of TNF-α converting enzyme (TACE) and provoked cardiomyocyte death. Conversely, TNF-a promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores (mPTP) as well as oxidative damage in cardiomyocytes. Together, RNase1 as well as inhibition of TACE provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-a interplay and significantly reduce or prevent the pathological outcome of ischemic heart injury. [ABSTRACT FROM PUBLISHER]
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- 2014
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11. P645 T2-mapping cardiac MRI for in vivo quantification of myocardial area-at-risk.
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Dongworth, RK, Campbell-Washburn, AE, Roberts, T, Yellon, DM, Lythgoe, MF, and Hausenloy, DJ
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CARDIAC magnetic resonance imaging ,GENE mapping ,REPERFUSION injury ,CARDIOTONIC agents ,MYOCARDIAL infarction ,LABORATORY mice - Abstract
Purpose: Novel therapeutic strategies are required to protect the heart against acute ischaemia-reperfusion injury (IRI). Assessing their cardioprotective efficacy requires measurement of infarct size (IS) and the "area-at-risk (AAR). T2-weighted cardiac magnetic resonance imaging (cMR) can delineate the AAR in vivo by detecting areas of oedema following IRI. However, clinical studies suggest that some cardioprotective interventions can reduce the extent of oedema measured by T2-weighted cMR, thereby affecting AAR measurement by this cMR method. We sought to investigate the validity of T2-mapping cMR for in vivo AAR quantification in hearts protected by ischaemic preconditioning (IPC).Methods: B6SV129 mice were subjected to in vivo acute IRI comprising LAD ligation for 30 minutes followed by 72 hours reperfusion. IPC-treated animals were subjected to a standard cardioprotective protocol of 5 minutes ischaemia and 5 minutes reperfusion prior to the main ischaemic insult. Following 3 days reperfusion, mice underwent cMR consisting of late-gadolinium enhancement and T2-mapping for assessment of infarct size and putative AAR, respectively. Immediately following cMR, hearts were excised and subjected to histological staining using triphenyl tetrazolium chloride and Evan's blue for infarct size and AAR, respectively. Assessment of cMR quantifications was performed by comparison with equivalent histological staining of left ventricular myocardial slices for infarct size (IS/LV%) and AAR (AAR/LV%).Results: cMR T2-maps of the myocardium in control and IPC-treated mice showed clearly defined regions of elevated T2-signal in spatially distinct regions of the myocardium. Comparison of T2-maps and histological staining for each slice demonstrated good agreement in the spatial localisation of AAR judged by T2-cMR and histology. Quantification of AAR from T2-maps showed no significant difference to AAR quantified by ‘gold-standard’ histological staining in control mice (AAR/LV% control: T2-cMR 60.4±2.4; versus histology 64.3±2.5: n=6, p>0.05). Importantly, T2-cMR significantly underestimated AAR in in IPC treated mice (AAR/LV% IPC: T2-cMR 46.0±13.2; versus histology 59.8±7.8: n=10, *p<0.05).Conclusions: Although the T2-mapping cMR protocol developed in here permits accurate quantification of myocardial area-at-risk in control mice following IRI; crucially, IPC significantly reduced the area of oedema and thus invalidated AAR measurement by T2-cMR in this model in the presence of IPC. Further investigation of the validity of T2-cMR for in vivo AAR assessment is now required for other therapeutic interventions. [ABSTRACT FROM AUTHOR]
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- 2014
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12. Interleukin 11 therapy causes acute left ventricular dysfunction.
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Sweeney M, O'Fee K, Villanueva-Hayes C, Rahman E, Lee M, Tam CN, Pascual-Navarro E, Maatz H, Lindberg EL, Vanezis K, Ramachandra CJ, Andrew I, Jennings ER, Lim WW, Widjaja AA, Carling D, Hausenloy DJ, Hubner N, Barton PJR, and Cook SA
- Abstract
Aims: Interleukin 11 (IL11) was initially thought important for platelet production, which led to recombinant IL11 being developed as a drug to treat thrombocytopenia. IL11 was later found to be redundant for haematopoiesis and its use in patients is associated with unexplained and severe cardiac side effects. Here we aim to identify, for the first time, direct cardiomyocyte toxicities associated with IL11, which was previously believed cardioprotective., Methods and Results: We injected recombinant mouse lL11 (rmIL11) into mice and studied its molecular effects in the heart using immunoblotting, qRT-PCR, bulk RNA-seq, single nuclei RNA-seq (snRNA-seq) and ATAC-seq. The physiological impact of IL11 was assessed by echocardiography in vivo and using cardiomyocyte contractility assays in vitro. To determine the activity of IL11 specifically in cardiomyocytes we made two cardiomyocyte-specific Il11ra1 knockout (CMKO) mouse models using either AAV9-mediated and Tnnt2-restricted (vCMKO) or Myh6 (m6CMKO) Cre expression and an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities. Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline: 62.4% ± 1.9; rmIL11: 32.6% ± 2.9, p<0.001, n=5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed upregulation of pro-inflammatory pathways (TNFα, NFκB and JAK/STAT) and perturbed calcium handling. snRNA-seq showed rmIL11-induced expression of stress factors (Ankrd1, Ankrd23, Xirp2), activator protein-1 (AP-1) transcription factor genes and Nppb in the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified the Ankrd1 and Nppb genes and loci enriched for stress-responsive, AP-1 transcription factor binding sites. Cardiomyocyte-specific effects were examined in vCMKO and m6CMKO mice, which were both protected from rmIL11-induced left ventricular impairment and molecular pathobiologies. In mechanistic studies, inhibition of JAK/STAT signalling with either ruxolitinib or tofacitinib prevented rmIL11-induced cardiac dysfunction., Conclusions: Injection of IL11 directly activates IL11RA/JAK/STAT3 in cardiomyocytes to cause acute heart failure. Our data overturn the earlier assumption that IL11 is cardioprotective and explain the serious cardiac side effects associated with IL11 therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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13. Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy.
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Phang RJ, Ritchie RH, Hausenloy DJ, Lees JG, and Lim SY
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- Humans, Myocytes, Cardiac metabolism, Diabetic Cardiomyopathies metabolism, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 metabolism, Heart Failure metabolism, Heart Diseases pathology
- Abstract
Patients with Type 2 diabetes mellitus (T2DM) frequently exhibit a distinctive cardiac phenotype known as diabetic cardiomyopathy. Cardiac complications associated with T2DM include cardiac inflammation, hypertrophy, fibrosis, and diastolic dysfunction in the early stages of the disease, which can progress to systolic dysfunction and heart failure. Effective therapeutic options for diabetic cardiomyopathy are limited and often have conflicting results. The lack of effective treatments for diabetic cardiomyopathy is due in part, to our poor understanding of the disease development and progression, as well as a lack of robust and valid preclinical human models that can accurately recapitulate the pathophysiology of the human heart. In addition to cardiomyocytes, the heart contains a heterogeneous population of non-myocytes including fibroblasts, vascular cells, autonomic neurons, and immune cells. These cardiac non-myocytes play important roles in cardiac homeostasis and disease, yet the effect of hyperglycaemia and hyperlipidaemia on these cell types is often overlooked in preclinical models of diabetic cardiomyopathy. The advent of human-induced pluripotent stem cells provides a new paradigm in which to model diabetic cardiomyopathy as they can be differentiated into all cell types in the human heart. This review will discuss the roles of cardiac non-myocytes and their dynamic intercellular interactions in the pathogenesis of diabetic cardiomyopathy. We will also discuss the use of sodium-glucose cotransporter 2 inhibitors as a therapy for diabetic cardiomyopathy and their known impacts on non-myocytes. These developments will no doubt facilitate the discovery of novel treatment targets for preventing the onset and progression of diabetic cardiomyopathy., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2023
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14. Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart.
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Lecour S, Du Pré BC, Bøtker HE, Brundel BJJM, Daiber A, Davidson SM, Ferdinandy P, Girao H, Gollmann-Tepeköylü C, Gyöngyösi M, Hausenloy DJ, Madonna R, Marber M, Perrino C, Pesce M, Schulz R, Sluijter JPG, Steffens S, Van Linthout S, Young ME, and Van Laake LW
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- Animals, Circadian Rhythm, Humans, Mammals, Translational Research, Biomedical, Cardiovascular Diseases, Cardiovascular System, Coronary Artery Disease, Myocardial Ischemia
- Abstract
Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes., Competing Interests: Conflict of interest: P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies. L.W.V.L. Outside the current work: consultancy fees to UMCU from Abbott, Medtronic, Vifor, and Novartis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)
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- 2022
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15. Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.
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Ramachandra CJA, Kp MMJ, Chua J, Hernandez-Resendiz S, Liehn EA, Knöll R, Gan LM, Michaëlsson E, Jonsson MKB, Ryden-Markinhuhta K, Bhat RV, Fritsche-Danielson R, Lin YH, Sadayappan S, Tang HC, Wong P, Shim W, and Hausenloy DJ
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- Animals, Cardiac Myosins genetics, Cardiac Myosins metabolism, Cardiomyopathy, Hypertrophic enzymology, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic physiopathology, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Line, Disease Models, Animal, Humans, Hypertrophy, Left Ventricular enzymology, Hypertrophy, Left Ventricular genetics, Hypertrophy, Left Ventricular physiopathology, Induced Pluripotent Stem Cells enzymology, Induced Pluripotent Stem Cells pathology, Male, Mice, Inbred C57BL, Mutation, Missense, Myocytes, Cardiac enzymology, Myocytes, Cardiac pathology, Myosin Heavy Chains genetics, Myosin Heavy Chains metabolism, Peroxidase metabolism, Phosphorylation, Reactive Oxygen Species metabolism, Tyrosine analogs & derivatives, Tyrosine metabolism, Mice, Cardiomyopathy, Hypertrophic drug therapy, Enzyme Inhibitors pharmacology, Hypertrophy, Left Ventricular drug therapy, Induced Pluripotent Stem Cells drug effects, Myocardial Contraction drug effects, Myocytes, Cardiac drug effects, Peroxidase antagonists & inhibitors, Ventricular Function, Left drug effects
- Abstract
Aims: Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM., Methods and Results: Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy., Conclusion: This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2022
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16. Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission.
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Kalkhoran SB, Kriston-Vizi J, Hernandez-Resendiz S, Crespo-Avilan GE, Rosdah AA, Lees JG, Costa JRSD, Ling NXY, Holien JK, Samangouei P, Chinda K, Yap EP, Riquelme JA, Ketteler R, Yellon DM, Lim SY, and Hausenloy DJ
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- Animals, Antioxidants pharmacology, Apoptosis drug effects, Disease Models, Animal, Dynamins metabolism, Female, HeLa Cells, Humans, Isolated Heart Preparation, Male, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Heart metabolism, Mitochondria, Heart pathology, Myocardial Infarction enzymology, Myocardial Infarction pathology, Myocardial Reperfusion Injury enzymology, Myocardial Reperfusion Injury pathology, Myocytes, Cardiac enzymology, Myocytes, Cardiac pathology, Oxidative Stress drug effects, Signal Transduction, Mice, Dynamins antagonists & inhibitors, Enzyme Inhibitors pharmacology, Hydralazine pharmacology, Mitochondria, Heart drug effects, Mitochondrial Dynamics drug effects, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects
- Abstract
Aims: Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission., Methods and Results: Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P<0.001)., Conclusion: We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine as a novel cardioprotective therapy for improving post-infarction outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2022
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17. Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies.
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Ramachandra CJA, Chua J, Cong S, Kp MMJ, Shim W, Wu JC, and Hausenloy DJ
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- Anthracyclines toxicity, Cardiomyopathies chemically induced, Cardiomyopathies genetics, Cardiomyopathies pathology, Cardiomyopathy, Dilated genetics, Cardiomyopathy, Dilated metabolism, Cardiomyopathy, Dilated pathology, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic metabolism, Cardiomyopathy, Hypertrophic pathology, Cardiotoxicity, Cell Differentiation, Cell Proliferation, Cells, Cultured, Diabetic Cardiomyopathies genetics, Diabetic Cardiomyopathies metabolism, Diabetic Cardiomyopathies pathology, Female, Gene Expression Regulation, Humans, Induced Pluripotent Stem Cells pathology, Mitochondria, Heart pathology, Myocytes, Cardiac pathology, Peripartum Period, Phenotype, Pregnancy, Pregnancy Complications, Cardiovascular genetics, Pregnancy Complications, Cardiovascular metabolism, Pregnancy Complications, Cardiovascular pathology, Cardiomyopathies metabolism, Energy Metabolism, Induced Pluripotent Stem Cells metabolism, Mitochondria, Heart metabolism, Myocytes, Cardiac metabolism
- Abstract
Normal cardiac contractile and relaxation functions are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human-induced pluripotent stem cells has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalized therapeutics for improving health outcomes in patients with cardiomyopathy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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18. Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction.
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Kompa AR, Greening DW, Kong AM, McMillan PJ, Fang H, Saxena R, Wong RCB, Lees JG, Sivakumaran P, Newcomb AE, Tannous BA, Kos C, Mariana L, Loudovaris T, Hausenloy DJ, and Lim SY
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- Animals, Antigens, Surface metabolism, Cell Proliferation, Cell Survival, Cells, Cultured, Culture Media, Conditioned metabolism, Disease Models, Animal, Fibrosis, Humans, Male, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardium metabolism, Neovascularization, Physiologic, Proteomics, Rats, Nude, Time Factors, Rats, Myocardial Infarction surgery, Myocardium pathology, Proteome, Regeneration, Secretome, Stem Cell Transplantation instrumentation, Stem Cells metabolism
- Abstract
Aims: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction., Methods and Results: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs., Conclusions: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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19. Effect of remote ischaemic conditioning on platelet reactivity and endogenous fibrinolysis in ST-elevation myocardial infarction: a substudy of the CONDI-2/ERIC-PPCI randomized controlled trial.
- Author
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Gorog DA, Farag M, Spinthakis N, Yellon DM, Bøtker HE, Kharbanda RK, and Hausenloy DJ
- Subjects
- Aged, Dual Anti-Platelet Therapy, Female, Humans, Male, Middle Aged, Regional Blood Flow, ST Elevation Myocardial Infarction blood, ST Elevation Myocardial Infarction diagnosis, ST Elevation Myocardial Infarction physiopathology, Single-Blind Method, Thrombosis blood, Thrombosis etiology, Time Factors, Treatment Outcome, Arm blood supply, Blood Platelets metabolism, Fibrinolysis, Ischemic Preconditioning adverse effects, Percutaneous Coronary Intervention adverse effects, Platelet Activation, ST Elevation Myocardial Infarction therapy, Thrombosis prevention & control
- Abstract
Aims: Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in animal models of myocardial infarction. Platelet thrombus formation is a critical determinant of outcome in ST-segment elevation myocardial infarction (STEMI). Whether the beneficial effects of RIC are related to thrombotic parameters is unclear., Methods and Results: In a substudy of the Effect of Remote Ischaemic Conditioning on clinical outcomes in STEMI patients undergoing Primary Percutaneous Coronary Intervention (ERIC-PPCI) trial, we assessed the effect of RIC on thrombotic status. Patients presenting with STEMI were randomized to immediate RIC consisting of an automated autoRIC™ cuff on the upper arm inflated to 200 mmHg for 5 min and deflated for 5 min for four cycles (n = 53) or sham (n = 47). Venous blood was tested at presentation, discharge (48 h) and 6-8 weeks, to assess platelet reactivity, coagulation, and endogenous fibrinolysis using the Global Thrombosis Test and thromboelastography. Baseline thrombotic status was similar in the two groups. At discharge, there was some evidence that the time to in vitro thrombotic occlusion under high shear stress was longer with RIC compared to sham (454 ± 105 s vs. 403 ± 105 s; mean difference 50.1 s; 95% confidence interval 93.7-6.4, P = 0.025), but this was no longer apparent at 6-8 weeks. There was no difference in clot formation or endogenous fibrinolysis between the study arms at any time point., Conclusion: RIC may reduce platelet reactivity in the first 48 h post-STEMI. Further research is needed to delineate mechanisms through which RIC may reduce platelet reactivity, and whether it may improve outcomes in patients with persistent high on-treatment platelet reactivity., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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20. Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart.
- Author
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Perrino C, Ferdinandy P, Bøtker HE, Brundel BJJM, Collins P, Davidson SM, den Ruijter HM, Engel FB, Gerdts E, Girao H, Gyöngyösi M, Hausenloy DJ, Lecour S, Madonna R, Marber M, Murphy E, Pesce M, Regitz-Zagrosek V, Sluijter JPG, Steffens S, Gollmann-Tepeköylü C, Van Laake LW, Van Linthout S, Schulz R, and Ytrehus K
- Subjects
- Animals, Comorbidity, Disease Models, Animal, Female, Humans, Male, Myocardial Ischemia diagnosis, Myocardial Ischemia physiopathology, Risk Assessment, Risk Factors, Sex Characteristics, Sex Factors, Species Specificity, Health Status Disparities, Myocardial Ischemia epidemiology, Translational Research, Biomedical
- Abstract
Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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21. Why did remote ischaemic conditioning not improve clinical outcomes in acute myocardial infarction in the CONDI-2/ERIC-PPCI trial?
- Author
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Hausenloy DJ and Bøtker HE
- Subjects
- Animals, Europe, Humans, Ischemic Preconditioning adverse effects, Ischemic Preconditioning mortality, Multicenter Studies as Topic, Myocardial Infarction diagnosis, Myocardial Infarction mortality, Myocardial Infarction physiopathology, Randomized Controlled Trials as Topic, Recovery of Function, Regional Blood Flow, Risk Factors, Treatment Outcome, Ischemic Preconditioning methods, Myocardial Infarction therapy, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention mortality, Upper Extremity blood supply, Ventricular Function, Left
- Published
- 2019
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22. Shining the spotlight on cardioprotection: beyond the cardiomyocyte.
- Author
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Davidson SM, Andreadou I, Garcia-Dorado D, and Hausenloy DJ
- Subjects
- Animals, Cardiovascular Agents adverse effects, Extracellular Vesicles metabolism, Humans, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Paracrine Communication, Platelet Activation drug effects, Signal Transduction, Treatment Outcome, Cardiovascular Agents therapeutic use, Extracellular Vesicles transplantation, Ischemic Preconditioning adverse effects, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects
- Published
- 2019
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23. The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection.
- Author
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Hausenloy DJ, Chilian W, Crea F, Davidson SM, Ferdinandy P, Garcia-Dorado D, van Royen N, Schulz R, and Heusch G
- Subjects
- Animals, Cardiovascular Agents adverse effects, Collateral Circulation drug effects, Humans, Ischemic Preconditioning, Myocardial, Microcirculation drug effects, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Myocardium metabolism, Neovascularization, Physiologic drug effects, No-Reflow Phenomenon metabolism, No-Reflow Phenomenon pathology, No-Reflow Phenomenon physiopathology, Treatment Outcome, Cardiovascular Agents therapeutic use, Coronary Circulation drug effects, Ischemic Postconditioning, Ischemic Preconditioning adverse effects, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Myocardium pathology, No-Reflow Phenomenon prevention & control
- Abstract
The coronary circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the coronary circulation, including microembolization of debris and release of soluble factors from the culprit lesion, impairment of endothelial integrity with subsequently increased permeability and oedema formation, platelet activation and leucocyte adherence, erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with eventual no-reflow, microvascular obstruction (MVO), and intramyocardial haemorrhage (IMH). Therefore, the coronary circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and carries, independently from infarct size, an unfavourable prognosis. MVO and IMH can be diagnosed by modern imaging technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the coronary circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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24. Cardiac innervation in acute myocardial ischaemia/reperfusion injury and cardioprotection.
- Author
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Hausenloy DJ, Bøtker HE, Ferdinandy P, Heusch G, Ng GA, Redington A, and Garcia-Dorado D
- Subjects
- Animals, Heart Failure metabolism, Heart Failure pathology, Heart Failure physiopathology, Humans, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Treatment Outcome, Heart innervation, Heart Failure prevention & control, Ischemic Preconditioning, Myocardial adverse effects, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Vagus Nerve Stimulation adverse effects
- Abstract
Acute myocardial infarction (AMI) and the heart failure (HF) that often complicates this condition, are among the leading causes of death and disability worldwide. To reduce myocardial infarct (MI) size and prevent heart failure, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). In this regard, targeting cardiac innervation may provide a novel therapeutic strategy for cardioprotection. A number of cardiac neural pathways mediate the beneficial effects of cardioprotective strategies such as ischaemic preconditioning and remote ischaemic conditioning, and nerve stimulation may therefore provide a novel therapeutic strategy for cardioprotection. In this article, we provide an overview of cardiac innervation and its impact on acute myocardial IRI, the role of extrinsic and intrinsic cardiac neural pathways in cardioprotection, and highlight peripheral and central nerve stimulation as a cardioprotective strategy with therapeutic potential for reducing MI size and preventing HF following AMI. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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25. Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities.
- Author
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Andreadou I, Cabrera-Fuentes HA, Devaux Y, Frangogiannis NG, Frantz S, Guzik T, Liehn EA, Gomes CPC, Schulz R, and Hausenloy DJ
- Subjects
- Animals, Anti-Inflammatory Agents adverse effects, Cardiovascular Agents adverse effects, Dendritic Cells drug effects, Dendritic Cells immunology, Dendritic Cells metabolism, Fibroblasts drug effects, Fibroblasts immunology, Fibroblasts metabolism, Heart Failure immunology, Heart Failure metabolism, Heart Failure pathology, Humans, Inflammation Mediators immunology, Inflammation Mediators metabolism, Lymphocytes drug effects, Lymphocytes immunology, Lymphocytes metabolism, Mast Cells drug effects, Mast Cells immunology, Mast Cells metabolism, Monocytes drug effects, Monocytes immunology, Monocytes metabolism, Myocardial Infarction immunology, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Reperfusion Injury immunology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardium metabolism, Myocardium pathology, Neutrophils drug effects, Neutrophils immunology, Neutrophils metabolism, Signal Transduction, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects, Anti-Inflammatory Agents therapeutic use, Cardiovascular Agents therapeutic use, Heart Failure prevention & control, Myocardial Infarction therapy, Myocardial Reperfusion Injury prevention & control, Myocardium immunology
- Abstract
New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling [changes in left ventricular (LV) size and function]. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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26. Nitroglycerine limits infarct size through S-nitrosation of cyclophilin D: a novel mechanism for an old drug.
- Author
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Bibli SI, Papapetropoulos A, Iliodromitis EK, Daiber A, Randriamboavonjy V, Steven S, Brouckaert P, Chatzianastasiou A, Kypreos KE, Hausenloy DJ, Fleming I, and Andreadou I
- Subjects
- Adult, Aged, Animals, Cyclophilins genetics, Cyclophilins metabolism, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, ApoE, Middle Aged, Myocardial Infarction enzymology, Myocardial Infarction pathology, Myocardial Reperfusion Injury enzymology, Myocardial Reperfusion Injury pathology, Myocytes, Cardiac enzymology, Myocytes, Cardiac pathology, Necrosis, Nitric Oxide Synthase Type III genetics, Nitric Oxide Synthase Type III metabolism, Nitrosation, Signal Transduction, Cyclophilins antagonists & inhibitors, Enzyme Inhibitors pharmacology, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Nitric Oxide Donors pharmacology, Nitroglycerin pharmacology
- Abstract
Aims: Nitroglycerine (NTG) given prior to an ischaemic insult exerts cardioprotective effects. However, whether administration of an acute low dose of NTG in a clinically relevant manner following an ischaemic episode limits infarct size, has not yet been explored., Methods and Results: Adult mice were subjected to acute myocardial infarction in vivo and then treated with vehicle or low-dose NTG prior to reperfusion. This treatment regimen minimized myocardial infarct size without affecting haemodynamic parameters but the protective effect was absent in mice rendered tolerant to the drug. Mechanistically, NTG was shown to nitrosate and inhibit cyclophilin D (CypD), and NTG administration failed to limit infarct size in CypD knockout mice. Additional experiments revealed lack of the NTG protective effect following genetic (knockout mice) or pharmacological inhibition (L-NAME treatment) of the endothelial nitric oxide synthase (eNOS). The protective effect of NTG was attributed to preservation of the eNOS dimer. Moreover, NTG retained its cardioprotective effects in a model of endothelial dysfunction (ApoE knockout) by preserving CypD nitrosation. Human ischaemic heart biopsies revealed reduced eNOS activity and exhibited reduced CypD nitrosation., Conclusion: Low-dose NTG given prior to reperfusion reduces myocardial infarct size by preserving eNOS function, and the subsequent eNOS-dependent S-nitrosation of CypD, inhibiting cardiomyocyte necrosis. This novel pharmacological action of NTG warrants confirmation in clinical studies, although our data in human biopsies provide promising preliminary results., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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27. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure.
- Author
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Madonna R, Van Laake LW, Botker HE, Davidson SM, De Caterina R, Engel FB, Eschenhagen T, Fernandez-Aviles F, Hausenloy DJ, Hulot JS, Lecour S, Leor J, Menasché P, Pesce M, Perrino C, Prunier F, Van Linthout S, Ytrehus K, Zimmermann WH, Ferdinandy P, and Sluijter JPG
- Subjects
- Consensus, Heart Failure pathology, Heart Failure physiopathology, Humans, Myocardial Ischemia pathology, Myocardial Ischemia physiopathology, Recovery of Function, Stem Cell Transplantation adverse effects, Treatment Outcome, Biomedical Research standards, Cardiology standards, Heart Failure surgery, Myocardial Ischemia surgery, Myocardium pathology, Regeneration, Stem Cell Transplantation standards, Tissue Engineering standards
- Abstract
Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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28. Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology.
- Author
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Sluijter JPG, Davidson SM, Boulanger CM, Buzás EI, de Kleijn DPV, Engel FB, Giricz Z, Hausenloy DJ, Kishore R, Lecour S, Leor J, Madonna R, Perrino C, Prunier F, Sahoo S, Schiffelers RM, Schulz R, Van Laake LW, Ytrehus K, and Ferdinandy P
- Subjects
- Animals, Biomarkers metabolism, Cardiology standards, Cell Fractionation standards, Cell- and Tissue-Based Therapy standards, Cell-Derived Microparticles pathology, Consensus, Exosomes pathology, Humans, Myocardial Ischemia metabolism, Myocardial Ischemia pathology, Predictive Value of Tests, Cardiology methods, Cell Fractionation methods, Cell- and Tissue-Based Therapy methods, Cell-Derived Microparticles metabolism, Cell-Derived Microparticles transplantation, Diagnostic Techniques, Cardiovascular standards, Exosomes metabolism, Exosomes transplantation, Myocardial Ischemia diagnosis, Myocardial Ischemia therapy
- Abstract
Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2018
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29. Melatonin as a cardioprotective therapy following ST-segment elevation myocardial infarction: is it really promising? Reply.
- Author
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Hausenloy DJ, Garcia-Dorado D, Erik Bøtker H, Davidson SM, Downey J, Engel FB, Jennings R, Lecour S, Leor J, Madonna R, Ovize M, Perrino C, Prunier F, Schulz R, Sluijter JPG, Van Laake LW, Vinten-Johansen J, Yellon DM, Ytrehus K, Heusch G, and Ferdinandy P
- Subjects
- Heart, Humans, Myocardial Infarction, Melatonin, ST Elevation Myocardial Infarction
- Published
- 2017
- Full Text
- View/download PDF
30. Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart.
- Author
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Perrino C, Barabási AL, Condorelli G, Davidson SM, De Windt L, Dimmeler S, Engel FB, Hausenloy DJ, Hill JA, Van Laake LW, Lecour S, Leor J, Madonna R, Mayr M, Prunier F, Sluijter JPG, Schulz R, Thum T, Ytrehus K, and Ferdinandy P
- Subjects
- Computational Biology standards, Databases, Genetic standards, Genetic Markers, Genetic Predisposition to Disease, Humans, Myocardial Ischemia diagnosis, Myocardial Ischemia therapy, Patient Selection, Phenotype, Predictive Value of Tests, Prognosis, Reproducibility of Results, Cardiology standards, Epigenesis, Genetic, Epigenomics standards, Gene Expression Profiling standards, Myocardial Ischemia genetics, Precision Medicine standards, Transcriptome
- Abstract
Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human 'diseasome'. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2017
- Full Text
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31. Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart.
- Author
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Hausenloy DJ, Garcia-Dorado D, Bøtker HE, Davidson SM, Downey J, Engel FB, Jennings R, Lecour S, Leor J, Madonna R, Ovize M, Perrino C, Prunier F, Schulz R, Sluijter JPG, Van Laake LW, Vinten-Johansen J, Yellon DM, Ytrehus K, Heusch G, and Ferdinandy P
- Subjects
- Animals, Cardiology standards, Cardiovascular Agents adverse effects, Coronary Artery Bypass standards, Disease Models, Animal, Heart Failure etiology, Heart Failure pathology, Heart Failure physiopathology, Humans, Ischemic Postconditioning methods, Ischemic Preconditioning adverse effects, Ischemic Preconditioning standards, Ischemic Preconditioning, Myocardial methods, Myocardial Reperfusion Injury etiology, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Percutaneous Coronary Intervention standards, Protective Factors, Risk Factors, ST Elevation Myocardial Infarction complications, ST Elevation Myocardial Infarction pathology, ST Elevation Myocardial Infarction physiopathology, Translational Research, Biomedical standards, Treatment Outcome, Cardiology methods, Cardiovascular Agents therapeutic use, Coronary Artery Bypass adverse effects, Heart Failure prevention & control, Ischemic Preconditioning methods, Myocardial Reperfusion Injury prevention & control, Percutaneous Coronary Intervention adverse effects, ST Elevation Myocardial Infarction therapy, Translational Research, Biomedical methods
- Abstract
Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic-however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial IRI., (The last two authors contributed equally to the paper as joint senior authors. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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- View/download PDF
32. Platelet inhibitors influence cardioprotection: importance in preclinical study design: reply.
- Author
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Lecour S, Schulz R, Ferdinandy P, and Hausenloy DJ
- Subjects
- Animals, Evaluation Studies as Topic, Myocardial Ischemia therapy, Translational Research, Biomedical
- Published
- 2015
- Full Text
- View/download PDF
33. ESC working group cellular biology of the heart: position paper: improving the preclinical assessment of novel cardioprotective therapies.
- Author
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Lecour S, Bøtker HE, Condorelli G, Davidson SM, Garcia-Dorado D, Engel FB, Ferdinandy P, Heusch G, Madonna R, Ovize M, Ruiz-Meana M, Schulz R, Sluijter JP, Van Laake LW, Yellon DM, and Hausenloy DJ
- Subjects
- Animals, Disease Models, Animal, Evaluation Studies as Topic, Myocardial Ischemia therapy, Translational Research, Biomedical
- Abstract
Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2014
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34. HIF-1 reduces ischaemia-reperfusion injury in the heart by targeting the mitochondrial permeability transition pore.
- Author
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Ong SG, Lee WH, Theodorou L, Kodo K, Lim SY, Shukla DH, Briston T, Kiriakidis S, Ashcroft M, Davidson SM, Maxwell PH, Yellon DM, and Hausenloy DJ
- Subjects
- Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Glycolysis, Hexokinase metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Male, Mice, Knockout, Mitochondria, Heart drug effects, Mitochondrial Permeability Transition Pore, Myocardial Infarction genetics, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Reperfusion Injury genetics, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardium pathology, Oxidative Stress, Prolyl-Hydroxylase Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Protein Stability, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Rats, Sprague-Dawley, Signal Transduction, Time Factors, Von Hippel-Lindau Tumor Suppressor Protein genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mitochondria, Heart metabolism, Mitochondrial Membrane Transport Proteins metabolism, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocardium metabolism
- Abstract
Aims: Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tolerance against acute myocardial ischaemia-reperfusion injury (IRI). However, the mechanism through which HIF-1 stabilization actually confers this cardioprotection is not clear. We investigated whether HIF-1α stabilization protects the heart against acute IRI by preventing the opening of the mitochondrial permeability transition pore (MPTP) and the potential mechanisms involved., Methods and Results: Stabilization of myocardial HIF-1 was achieved by pharmacological inhibition of prolyl hydroxylase (PHD) domain-containing enzyme using GSK360A or using cardiac-specific ablation of von Hippel-Lindau protein (VHL(fl/fl)) in mice. Treatment of HL-1 cardiac cells with GSK360A stabilized HIF-1, increased the expression of HIF-1 target genes pyruvate dehydrogenase kinase-1 (PDK1) and hexokinase II (HKII), and reprogrammed cell metabolism to aerobic glycolysis, thereby resulting in the production of less mitochondrial oxidative stress during IRI, and less MPTP opening, effects which were shown to be dependent on HKII. These findings were further confirmed when HIF-1 stabilization in the rat and murine heart resulted in smaller myocardial infarct sizes (both in vivo and ex vivo), decreased mitochondrial oxidative stress, and inhibited MPTP opening following IRI, effects which were also found to be dependent on HKII., Conclusions: We have demonstrated that acute HIF-1α stabilization using either a pharmacological or genetic approach protected the heart against acute IRI by promoting aerobic glycolysis, decreasing mitochondrial oxidative stress, activating HKII, and inhibiting MPTP opening., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)
- Published
- 2014
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35. Interaction of the heart and its close and distant neighbours: report of the Meeting of the ESC Working Groups Myocardial Function and Cellular Biology.
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Hirsch E, Hilfiker-Kleiner D, Balligand JL, Tarone G, De Windt L, Bauersachs J, Ferdinandy P, Davidson S, Hausenloy DJ, and Schulz R
- Subjects
- Animals, Endothelial Cells physiology, Exosomes physiology, Fibroblasts physiology, Heart Diseases physiopathology, Heart Diseases therapy, Humans, Ischemic Preconditioning, Myocardial, Cell Communication, Myocytes, Cardiac physiology
- Published
- 2013
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36. Cardioprotection in the aging, diabetic heart: the loss of protective Akt signalling.
- Author
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Whittington HJ, Harding I, Stephenson CI, Bell R, Hausenloy DJ, Mocanu MM, and Yellon DM
- Subjects
- Animals, Blood Glucose analysis, Glycated Hemoglobin analysis, Humans, Male, Myocardial Infarction etiology, Oxidative Stress, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phenotype, Phosphorylation, Rats, Rats, Wistar, Transcription Factors physiology, Aging physiology, Diabetes Mellitus physiopathology, Ischemic Preconditioning, Myocardial, Myocardial Reperfusion Injury etiology, Proto-Oncogene Proteins c-akt physiology, Signal Transduction physiology
- Abstract
Aims: Old age and diabetes are risk factors that often coexist increasing the vulnerability of the heart to the lethal effects of ischaemia-reperfusion injury (IRI). However, to our knowledge, no investigations have examined IRI and cardioprotective signalling in animal models bearing these co-morbidities concomitantly. The ability of the heart to recover following IRI is greatly dependent on its innate cardioprotective potential, in which a central role is played by Akt. We aimed to investigate in an aging diabetic rat model, the susceptibility of the heart to IRI, the achievability of ischaemic preconditioning (IPC) against this lethal event, and the changes in Akt signalling, as the main prosurvival intracellular pathway., Methods and Results: Our data showed that the isolated hearts of aged, diabetic Goto-Kakizaki rats were more susceptible to sub-lethal injury and not amenable to cardioprotection via IPC, compared with younger diabetic rat hearts. Western blot analysis of the heart tissue suggested a chronic up-regulation of Akt phosphorylation, and reduced expression of the mitochondrial regulator PGC-1α and of the anti-oxidant enzyme catalase, potentially due to the Akt up-regulation. Moreover, no further activation of Akt could be achieved following IPC., Conclusion: An increased susceptibility to IRI in the aged, diabetic heart could be a consequence of impaired Akt signalling due to chronic Akt phosphorylation. Additional Akt phosphorylation required for IPC protection may therefore not be possible in the aged, diabetic rat heart and may explain why this cardioprotective manoeuvre cannot be achieved in these hearts.
- Published
- 2013
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37. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology.
- Author
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Hausenloy DJ, Erik Bøtker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, Lecour S, van Laake LW, Madonna R, Ruiz-Meana M, Schulz R, Sluijter JP, Yellon DM, and Ovize M
- Subjects
- Animals, Cardiopulmonary Bypass, Cardiopulmonary Resuscitation, Collateral Circulation, Coronary Artery Bypass, Coronary Circulation, Coronary Disease complications, Disease Models, Animal, Heart Transplantation, Humans, Signal Transduction, Coronary Disease therapy, Myocardial Reperfusion Injury prevention & control
- Abstract
Coronary heart disease (CHD) is the leading cause of death and disability worldwide. Despite current therapy, the morbidity and mortality for patients with CHD remains significant. The most important manifestations of CHD arise from acute myocardial ischaemia-reperfusion injury (IRI) in terms of cardiomyocyte death and its long-term consequences. As such, new therapeutic interventions are required to protect the heart against the detrimental effects of acute IRI and improve clinical outcomes. Although a large number of cardioprotective therapies discovered in pre-clinical studies have been investigated in CHD patients, few have been translated into the clinical setting, and a significant number of these have failed to show any benefit in terms of reduced myocardial infarction and improved clinical outcomes. Because of this, there is currently no effective therapy for protecting the heart against the detrimental effects of acute IRI in patients with CHD. One major factor for this lack of success in translating cardioprotective therapies into the clinical setting can be attributed to problems with the clinical study design. Many of these clinical studies have not taken into consideration the important data provided from previously published pre-clinical and clinical studies. The overall aim of this ESC Working Group Cellular Biology of the Heart Position Paper is to provide recommendations for optimizing the design of clinical cardioprotection studies, which should hopefully result in new and effective therapeutic interventions for the future benefit of CHD patients.
- Published
- 2013
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38. The shape of things to come: mitochondrial fusion and fission in the adult heart.
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Hall AR and Hausenloy DJ
- Subjects
- Animals, Mitochondrial Permeability Transition Pore, GTP Phosphohydrolases metabolism, Mitochondria metabolism, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Membranes metabolism, Myocytes, Cardiac cytology, Optic Atrophy, Autosomal Dominant physiopathology
- Published
- 2012
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39. Cardioprotection during cardiac surgery.
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Hausenloy DJ, Boston-Griffiths E, and Yellon DM
- Subjects
- Coronary Artery Disease surgery, Humans, Ischemic Postconditioning methods, Ischemic Preconditioning, Myocardial methods, Myocardial Infarction etiology, Cardiotonic Agents therapeutic use, Coronary Artery Bypass, Myocardial Infarction prevention & control, Postoperative Complications prevention & control, Reperfusion Injury prevention & control
- Abstract
Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. For a large number of patients with CHD, coronary artery bypass graft (CABG) surgery remains the preferred strategy for coronary revascularization. Over the last 10 years, the number of high-risk patients undergoing CABG surgery has increased significantly, resulting in worse clinical outcomes in this patient group. This appears to be related to the ageing population, increased co-morbidities (such as diabetes, obesity, hypertension, stroke), concomitant valve disease, and advances in percutaneous coronary intervention which have resulted in patients with more complex coronary artery disease undergoing surgery. These high-risk patients are more susceptible to peri-operative myocardial injury and infarction (PMI), a major cause of which is acute global ischaemia/reperfusion injury arising from inadequate myocardial protection during CABG surgery. Therefore, novel therapeutic strategies are required to protect the heart in this high-risk patient group. In this article, we review the aetiology of PMI during CABG surgery, its diagnosis and clinical significance, and the endogenous and pharmacological therapeutic strategies available for preventing it. By improving cardioprotection during CABG surgery, we may be able to reduce PMI, preserve left ventricular systolic function, and reduce morbidity and mortality in these high-risk patients with CHD.
- Published
- 2012
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40. Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.
- Author
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Hausenloy DJ, Lim SY, Ong SG, Davidson SM, and Yellon DM
- Subjects
- Animals, Cell Death, Cell Hypoxia, Peptidyl-Prolyl Isomerase F, Cyclophilins antagonists & inhibitors, Cyclophilins deficiency, Cyclophilins genetics, Cyclosporine pharmacology, Disease Models, Animal, Enzyme Activation, Male, Mice, Mice, Knockout, Mitochondria, Heart drug effects, Mitochondria, Heart pathology, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Permeability Transition Pore, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocytes, Cardiac drug effects, Myocytes, Cardiac pathology, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Reactive Oxygen Species metabolism, Time Factors, Cyclophilins metabolism, Ischemic Preconditioning, Myocardial, Mitochondria, Heart metabolism, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac metabolism, Signal Transduction drug effects
- Abstract
Aims: It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2., Methods and Results: Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout. We have demonstrated that under basal conditions, non-pathological mPTP opening occurs (indicated by the percent reduction in mitochondrial calcein fluorescence). This effect was greater in WT cardiomyocytes compared with CYPD-/- ones (53 ± 2% WT vs. 17 ± 3% CYPD-/-; P < 0.01) and was augmented by hypoxic preconditioning (HPC) (70 ± 9% WT vs. 56 ± 1% CYPD-/-; P < 0.01). HPC reduced cell death following simulated ischaemia-reperfusion injury in WT (23.2 ± 3.5% HPC vs. 43.7 ± 3.2% WT; P < 0.05) but not CYPD-/- cardiomyocytes (19.6 ± 1.4% HPC vs. 24.4 ± 2.6% control; P > 0.05). HPC generated mitochondrial ROS in WT (four-fold increase; P < 0.05) but not CYPD-/- cardiomyocytes. HPC induced significant Akt phosphorylation in WT cardiomyocytes (two-fold increase; P < 0.05), an effect which was abrogated by ciclosporin-A (a CYPD inhibitor) and N-2-mercaptopropionyl glycine (a ROS scavenger). Finally, in vivo IPC of adult murine hearts resulted in significant phosphorylation of Akt and Erk1/2 in WT but not CYPD-/- hearts., Conclusion: The CYPD component of the mPTP is required by IPC to generate mitochondrial ROS and phosphorylate Akt and Erk1/2, major steps in the IPC signalling pathway.
- Published
- 2010
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41. Mitochondrial morphology and cardiovascular disease.
- Author
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Ong SB and Hausenloy DJ
- Subjects
- Animals, Apoptosis, Autophagy, Cardiovascular Diseases metabolism, Cardiovascular Diseases therapy, Energy Metabolism, Humans, Mitochondria, Heart metabolism, Mitochondrial Membranes metabolism, Mitochondrial Membranes pathology, Mitochondrial Proteins metabolism, Myocardium metabolism, Signal Transduction, Cardiovascular Diseases pathology, Mitochondria, Heart pathology, Myocardium pathology
- Abstract
Mitochondria are dynamic and are able to interchange their morphology between elongated interconnected mitochondrial networks and a fragmented disconnected arrangement by the processes of mitochondrial fusion and fission, respectively. Changes in mitochondrial morphology are regulated by the mitochondrial fusion proteins (mitofusins 1 and 2, and optic atrophy 1) and the mitochondrial fission proteins (dynamin-related peptide 1 and mitochondrial fission protein 1) and have been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy, although the majority of studies have been largely confined to non-cardiac cells. Despite the unique arrangement of mitochondria in the adult heart, emerging data suggest that changes in mitochondrial morphology may be relevant to various aspects of cardiovascular biology-these include cardiac development, the response to ischaemia-reperfusion injury, heart failure, diabetes mellitus, and apoptosis. Interestingly, the machinery required for altering mitochondrial shape in terms of the mitochondrial fusion and fission proteins are all present in the adult heart, but their physiological function remains unclear. In this article, we review the current developments in this exciting new field of mitochondrial biology, the implications for cardiovascular physiology, and the potential for discovering novel therapeutic strategies for treating cardiovascular disease.
- Published
- 2010
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42. Not just the powerhouse of the cell: emerging roles for mitochondria in the heart.
- Author
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Hausenloy DJ and Ruiz-Meana M
- Subjects
- Animals, Calcium metabolism, Energy Metabolism, Heart Diseases pathology, Heart Diseases prevention & control, Humans, Ischemic Preconditioning, Myocardial, Mitochondria, Heart pathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury prevention & control, Myocardium pathology, Nitric Oxide metabolism, Oxidative Stress, Phenotype, Signal Transduction, Heart Diseases metabolism, Mitochondria, Heart metabolism, Myocardium metabolism
- Published
- 2010
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43. Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology.
- Author
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Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, and Schulz R
- Subjects
- Algorithms, Animals, Cardiology, Europe, Evidence-Based Medicine, Humans, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardium pathology, Risk Assessment, Risk Factors, Signal Transduction, Societies, Medical, Treatment Outcome, Cardiovascular Agents therapeutic use, Ischemic Preconditioning, Myocardial adverse effects, Ischemic Preconditioning, Myocardial methods, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocardium metabolism
- Abstract
Ischaemic postconditioning (brief periods of ischaemia alternating with brief periods of reflow applied at the onset of reperfusion following sustained ischaemia) effectively reduces myocardial infarct size in all species tested so far, including humans. Ischaemic postconditioning is a simple and safe manoeuvre, but because reperfusion injury is initiated within minutes of reflow, postconditioning must be applied at the onset of reperfusion. The mechanisms of protection by postconditioning include: formation and release of several autacoids and cytokines; maintained acidosis during early reperfusion; activation of protein kinases; preservation of mitochondrial function, most strikingly the attenuation of opening of the mitochondrial permeability transition pore (MPTP). Exogenous recruitment of some of the identified signalling steps can induce cardioprotection when applied at the time of reperfusion in animal experiments, but more recently cardioprotection was also observed in a proof-of-concept clinical trial. Indeed, studies in patients with an acute myocardial infarction showed a reduction of infarct size and improved left ventricular function when they underwent ischaemic postconditioning or pharmacological inhibition of MPTP opening during interventional reperfusion. Further animal studies and large-scale human studies are needed to determine whether patients with different co-morbidities and co-medications respond equally to protection by postconditioning. Also, our understanding of the underlying mechanisms must be improved to develop new therapeutic strategies to be applied at reperfusion with the ultimate aim of limiting the burden of ischaemic heart disease and potentially providing protection for other organs at risk of reperfusion injury, such as brain and kidney.
- Published
- 2010
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44. Cardioprotective growth factors.
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Hausenloy DJ and Yellon DM
- Subjects
- Animals, Cytokines metabolism, Genetic Therapy, Humans, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins therapeutic use, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardium pathology, Protein Kinases metabolism, Receptor Protein-Tyrosine Kinases metabolism, Signal Transduction, Stem Cell Transplantation, Stem Cells metabolism, Urocortins metabolism, Intercellular Signaling Peptides and Proteins metabolism, Myocardial Reperfusion Injury prevention & control, Myocardium metabolism, Transforming Growth Factor beta metabolism
- Abstract
Many of the originally identified cardiovascular 'growth factors' have been demonstrated to exert a diverse variety of actions within the cardiovascular system, the majority of which are unrelated to their initially proposed mechanism of action. Interestingly, several of these growth factors have been demonstrated to protect the cardiomyocyte from the detrimental effects of acute ischaemia-reperfusion injury, through the activation of a variety of cell-surface receptors and the subsequent recruitment of a number of intracellular signal transduction pathways, which include components of the reperfusion injury salvage kinase pathway. This article will review several of these cardioprotective growth factors with respect to their ability to confer direct myocardial protection, focusing on the underlying signalling pathways involved and their potential for clinical application.
- Published
- 2009
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45. Remote ischaemic preconditioning: underlying mechanisms and clinical application.
- Author
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Hausenloy DJ and Yellon DM
- Subjects
- Animals, Humans, Ischemic Preconditioning, Myocardial, Myocardial Infarction metabolism, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury prevention & control, Reperfusion Injury metabolism, Treatment Outcome, Ischemic Preconditioning, Myocardial Infarction prevention & control, Myocardium metabolism, Reperfusion Injury prevention & control, Signal Transduction
- Abstract
Remote ischaemic preconditioning (RIPC) represents a strategy for harnessing the body's endogenous protective capabilities against the injury incurred by ischaemia and reperfusion. It describes the intriguing phenomenon in which transient non-lethal ischaemia and reperfusion of one organ or tissue confers resistance to a subsequent episode of lethal ischaemia reperfusion injury in a remote organ or tissue. In its original conception, it described intramyocardial protection, which could be relayed from the myocardium served by one coronary artery to another. It soon became apparent that myocardial infarct size could be dramatically reduced by applying brief ischaemia and reperfusion to an organ or tissue remote from the heart before the onset of myocardial infarction. The concept of remote organ protection has now been extended beyond that of solely protecting the heart to providing a general form of inter-organ protection against ischaemia-reperfusion injury. This article reviews the history and evolution of the phenomenon that is RIPC, the potential mechanistic pathways underlying its cardioprotective effect, and its emerging application in the clinical setting.
- Published
- 2008
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46. Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore.
- Author
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Lim SY, Davidson SM, Hausenloy DJ, and Yellon DM
- Subjects
- Animals, Bradykinin pharmacology, Peptidyl-Prolyl Isomerase F, Cyclophilins genetics, Cyclophilins metabolism, Cyclosporine pharmacology, Diazoxide pharmacology, Enzyme Inhibitors pharmacology, Female, Lactones pharmacology, Male, Mice, Mice, Knockout, Mitochondria, Heart ultrastructure, Mitochondrial Permeability Transition Pore, Models, Animal, Myocardial Ischemia pathology, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocardium pathology, Spiro Compounds pharmacology, Vasodilator Agents pharmacology, Ischemic Preconditioning, Myocardial, Mitochondria, Heart metabolism, Mitochondrial Membrane Transport Proteins physiology, Myocardial Ischemia metabolism, Myocardial Reperfusion Injury prevention & control
- Abstract
Objective: The opening of the mitochondrial permeability transition pore (mPTP) at the time of myocardial reperfusion is a critical determinant of cell death. Emerging studies suggest that suppression of mPTP opening may underlie the cardioprotection elicited by both ischemic preconditioning (IPC) and postconditioning (IPost). To further evaluate the role of the mPTP in cardioprotection, we hypothesized that hearts deficient in cyclophilin-D (CYP-D-/-), a key component of the mPTP, will be resistant to cardioprotection conferred by ischemic and pharmacological preconditioning and postconditioning., Methods and Results: Male/female wild type or CYP-D-/- mice were subjected to 30 min of ischemia and 120 min of reperfusion. In wild type mice subjected to in vivo myocardial ischemia-reperfusion injury, a significant reduction in myocardial infarct size was observed with the following treatments (n>/=6/group; P<0.05): (1) IPC (28+/-4% vs. 46.2+/-4% in control); (2) Diazoxide (5 mg/kg) pre-treatment (26.4+/-3% vs. 54+/-10% in vehicle control); (3) IPost-1 or IPost-2, three or six 10-s cycles of ischemia-reperfusion (27.2+/-3% and 32+/-4%, respectively vs. 46.2+/-4% in control); (4) Bradykinin (40 mug/kg) (28.3+/-1% vs. 48+/-4% in vehicle control); (5) cyclosporin-A (10 mg/kg) (32.3+/-3% vs. 48+/-4% in vehicle control) (6) sanglifehrin-A (25 mg/kg) (29.3+/-3% vs. 48+/-4% in vehicle control). Interestingly, however, no infarct-limiting effects were demonstrated in CYP-D-/- mice with the same treatment protocols: (27.9+/-5% in control vs. 31.2+/-7% with IPC, 30.2+/-5% with IPost-1, 24.7+/-8% with IPost-2; 30.1+/-4% in vehicle control vs. 26.4+/-7% with diazoxide; 24.6+/-4% in vehicle control vs. 24.9+/-5% with bradykinin, 26.8+/-7% with cyclosporin-A, 32.5+/-6% with sanglifehrin-A: n>/=6/group: P>0.05)., Conclusion: This study demonstrates that the mPTP plays a critical role in the cardioprotection elicited by ischemic and pharmacological preconditioning and postconditioning.
- Published
- 2007
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47. Survival kinases in ischemic preconditioning and postconditioning.
- Author
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Hausenloy DJ and Yellon DM
- Subjects
- Animals, Enzyme Activators metabolism, Humans, MAP Kinase Signaling System, Mitochondrial Membrane Transport Proteins, Mitochondrial Permeability Transition Pore, Ischemic Preconditioning, Myocardial, Myocardial Infarction enzymology, Myocardium enzymology, Protein Kinases physiology, Signal Transduction physiology
- Abstract
Despite nearly twenty years of research into the field of ischemic preconditioning, the actual mechanism of protection remains unclear. However, much progress has been made in elucidating the signal transduction pathways that convey the extracellular signal initiated by the preconditioning stimulus to the intracellular targets of cardioprotection, with many of these pathways involving the activation of a diverse array of survival protein kinase cascades. The powerful protective benefits of ischemic preconditioning have not yet been realised in the clinical arena, not least because of the prerequisite for any preconditioning intervention to be applied prior to the onset of index ischemia, which in the case of an acute myocardial infarction is difficult to institute. In this regard, the newly described phenomenon of ischemic postconditioning, which comprises a cardioprotective intervention that can be applied at the time of myocardial reperfusion, offers a far more attractive and amenable approach to myocardial protection. Interestingly, certain survival protein kinase cascades recruited at the time of myocardial reperfusion appear to be shared by both ischemic preconditioning and postconditioning, thereby offering a potentially common target of cardioprotection. The often disputed roles these different protein kinases play in mediating the cardioprotective effects of ischemic preconditioning and postconditioning are reviewed in this article, and include protein kinases C, G, and A, members of the MAPK family (Erk1/2, p38, JNK and BMK1), the PI3K-Akt cascade, and the JAK-STAT pathway.
- Published
- 2006
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48. Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning.
- Author
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Hausenloy DJ, Mocanu MM, and Yellon DM
- Subjects
- Animals, Blotting, Western methods, Enzyme Inhibitors pharmacology, Flavonoids pharmacology, Male, Mitogen-Activated Protein Kinases analysis, Mitogen-Activated Protein Kinases antagonists & inhibitors, Perfusion, Phosphatidylinositol 3-Kinases analysis, Phosphoinositide-3 Kinase Inhibitors, Rats, Rats, Sprague-Dawley, Ribosomal Protein S6 Kinases, 70-kDa antagonists & inhibitors, Sirolimus pharmacology, Ischemic Preconditioning, Myocardial, MAP Kinase Signaling System physiology, Myocardial Infarction metabolism, Myocardial Reperfusion, Myocardium enzymology, Phosphatidylinositol 3-Kinases metabolism
- Abstract
Objectives: Recruitment of the survival kinase cascades, PI3K-Akt and Raf-MEK1/2-Erk1/2, at the time of reperfusion, following a lethal ischemic insult, may mediate the protection associated with ischemic preconditioning (IPC). The exact interplay between these two kinase cascades in mediating this effect is not clear. We examine the 'cross-talk' between these kinase cascades in their contribution to IPC-induced protection., Methods and Results: In isolated perfused rat hearts subjected to 35 min of lethal ischemia +/- ischemic preconditioning, the phosphorylation states of Akt, Erk1/2, p70S6K were determined after 15 min of reperfusion, and infarct size was measured after 120 min of reperfusion. IPC induced a threefold increase in Akt, Erk1/2, and p70S6K phosphorylation, at reperfusion. We found that inhibiting the PI3K-Akt (using LY294008) at reperfusion induced the phosphorylation of Erk1/2-p70S6K, and conversely, that inhibiting the MEK1/2-Erk1/2 pathway (using PD 98059) at reperfusion, induced the phosphorylation of Akt, suggesting 'cross-talk' between the two kinase pathways. However, this effect was not accompanied by a reduction in infarct size (43.1 +/- 7.2% with LY 294008 and 57.7 +/- 7.0% with PD 98059 vs. 46.3 +/- 5.8% in control; P = NS), suggesting that both the kinase cascades may need to be activated to mediate IPC-induced protection. IPC reduced the infarct-risk volume ratio to 17.8 +/- 2.3% from 46.3 +/- 5.8% in control (P < 0.01). Inhibiting p70S6K, a kinase situated downstream of both PI3K and Erk1/2, using rapamycin, abolished IPC-induced protection (46.0 +/- 7.7% with IPC+RAPA vs. 17.8 +/- 2.3% with IPC; P < 0.01)., Conclusions: We report that, the survival kinase cascades PI3K-Akt and MEK1/2-Erk1/2, which are recruited at the time of reperfusion in response to ischemic preconditioning, exhibit 'cross-talk' such that inhibiting one cascade activates the other and vice versa. Furthermore, at the time of reperfusion, these kinase cascades mediate IPC-induced protection, by acting in concert via p70S6K., (Copyright 2004 European Society of Cardiology)
- Published
- 2004
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49. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway.
- Author
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Hausenloy DJ and Yellon DM
- Subjects
- Apoptosis, Cell Nucleus metabolism, Enzyme Activation, Humans, MAP Kinase Signaling System, Mitochondria, Heart metabolism, Myocardial Ischemia enzymology, Myocardial Reperfusion Injury pathology, Myocardium pathology, Phosphatidylinositol 3-Kinases metabolism, Myocardial Reperfusion Injury prevention & control, Myocardium metabolism, Signal Transduction
- Abstract
Reperfusion is a pre-requisite to salvaging viable myocardium, following an acute myocardial infarction. Reperfusion of ischaemic myocardium, however, is not without risk, as the act of reperfusion itself can paradoxically result in myocyte death: a phenomenon termed lethal reperfusion-induced injury. Therapeutic strategies that target and attenuate reperfusion-induced cell death may provide novel pharmacological agents, which can be used as an adjunct to current reperfusion therapy, to limit myocardial infarction. Recent evidence has implicated apoptotic cell death during the phase of reperfusion as an important contributor to lethal reperfusion-induced injury. Targeting anti-apoptotic mechanisms of cellular protection at the time of reperfusion may therefore offer a potential approach to attenuating reperfusion-induced cell death. In this regard, ischaemia-reperfusion has been shown to activate the anti-apoptotic pro-survival kinase signalling cascades, phosphatidylinositol-3-OH kinase (PI3K)-Akt and p42/p44 extra-cellular signal-regulated kinases (Erk 1/2), both of which have been implicated in cellular survival. Activating these pro-survival kinase cascades at the time of reperfusion has been demonstrated to confer protection against reperfusion-induced injury. We and others have shown that insulin, insulin-like growth factor-1 (IGF-1), transforming growth factor-beta1 (TGF-beta1), cardiotrophin-1 (CT-1), urocortin, atorvastatin and bradykinin protect the heart, by activating the PI3K-Akt and/or Erk 1/2 kinase cascades, when given at the commencement of reperfusion, following a lethal ischaemic insult. Pharmacological manipulation and up-regulation of these pro-survival kinase cascades, which we refer to as the Reperfusion Injury Salvage Kinase (RISK) pathway, as an adjunct to reperfusion may therefore protect the myocardium from lethal reperfusion-induced cell death and provide a novel strategy to salvaging viable myocardium and limiting infarct size.
- Published
- 2004
- Full Text
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50. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury.
- Author
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Hausenloy DJ, Duchen MR, and Yellon DM
- Subjects
- Animals, Ion Channels metabolism, Male, Microscopy, Confocal, Mitochondrial Membrane Transport Proteins, Mitochondrial Permeability Transition Pore, Myocardial Infarction metabolism, Myocardial Reperfusion, Rats, Rats, Sprague-Dawley, Intracellular Membranes metabolism, Ion Channels drug effects, Lactones therapeutic use, Mitochondria, Heart metabolism, Myocardial Reperfusion Injury prevention & control, Spiro Compounds therapeutic use
- Abstract
Objective: The opening of the mitochondrial permeability transition pore (mPTP) in the first few minutes of post-ischaemic reperfusion is a critical determinant of reperfusion-induced cell death. We hypothesised that the novel immunosuppressant, sanglifehrin-A (SFA), given at the time of reperfusion, protects the myocardium from ischaemia-reperfusion injury, by suppressing mPTP opening., Methods: Isolated perfused rat hearts were subjected to 35 min ischaemia/120 min reperfusion, and were treated with (1) SFA (1.0 microM) or (2) DMSO vehicle for the first 15 min of reperfusion or (3) SFA (1.0 microM) after the first 15 min of reperfusion. We examined the effect of SFA on mPTP opening directly, using a myocyte model of oxidative stress. Laser illumination of adult rat myocytes loaded with the fluorophore, TMRM, generates oxidative stress, which induces mPTP opening (represented by mitochondrial membrane depolarisation) followed by rigour contracture., Results: In the isolated perfused heart model, SFA, given during the first 15 min of post-ischaemic reperfusion, reduced the infarct-risk volume ratio from 43.9+/-2.5% in the control group to 23.8+/-4.2% with SFA (p=0.001). However, when SFA was given after the first 15 min of reperfusion, there was no change in infarct size (43.8+/-5.7% with SFA vs. 43.9+/-2.5% in control; p=NS), suggesting that SFA has to be present during the first 15 min of reperfusion to induce protection. In the isolated adult myocyte model, SFA was shown to inhibit mPTP opening in the setting of oxidative stress, represented by an increase in the ROS threshold required to induce: mitochondrial membrane depolarisation (from 269+/-21 to 777+/-100 s; p<0.001) and rigour contracture (from 613+/-14 to 1329+/-129 s; p<0.001)., Conclusions: Inhibiting mPTP opening during the first few minutes of reperfusion, using sanglifehrin-A, limits infarct size and protects myocytes from oxidative stress.
- Published
- 2003
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