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In this work, aluminium nitride (AlN) films were deposited on silicon substrates buffered by an epitaxial AlN thin film for surface acoustic wave (SAW) applications. The films were deposited by dc magnetron sputtering (dcMS) and high power impulse magnetron sputtering (HiPIMS) deposition techniques. The structural properties of AlN films were investigated using x-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy and atomic force microscopy. In both cases of films deposited by dcMS and HiPIMS, the XRD results showed that the obtained films are oriented, with full width at half maximum rocking curves of around 1°. Raman spectroscopy revealed higher residual stress relaxation in the AlN epilayers grown by HiPIMS compared to AlN grown by dcMS, highlighted by a blue shift in the E2(high) Raman mode. The SAW measurements indicated an insertion loss of AlN-SAW devices of about 53 and 35 dB for the AlN films deposited by dcMS and HiPIMS respectively. The relation between the structural properties of AlN and the characteristics of AlN-SAW devices were correlated and discussed. [ABSTRACT FROM AUTHOR]

Dyslipidemia is the most significant risk factor for cardiovascular diseases (CVDs) Secondary dyslipidemia: its treatments and association with atherosclerosis. Glob Health Med, Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies. The current treatment strategies for managing dyslipidemia focus on reducing low-density lipoprotein cholesterol (LDL-C) to minimize the risks of atherosclerosis and myocardial infarction (MI). Homozygous Familial Hypercholesterolemia (HoFH) is an inherited autosomal dominant disease caused by a mutation in the LDL receptor (LDLr), which can lead to extremely high levels of LDL-C The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr(-/-) Mice with Obesity, The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity. Although statin therapy has been the primary treatment for dyslipidemia, HoFH patients do not respond well to statins, requiring alternative therapies. Microsomal triglyceride transfer protein (MTP) inhibition has emerged as a potential therapeutic target for treating HoFH. MTP is primarily responsible for transferring triglyceride and other lipids into apolipoprotein B (ApoB) during the assembly of very low-density lipoprotein (VLDL) particles in the liver. Lomitapide, an inhibitor of MTP, has been approved for treatingof HoFH adults. Unlike statins, lomitapide does not act on the LDLr to reduce cholesterol. Instead, lomitapide lowers the levels of ApoB-containing proteins, primarily VLDL, eventually decreasing LDL-C levels. Studies have shown that lomitapide can reduce LDL-C levels by more than 50% in patients with HoFH who have failed to respond adequately to other treatments. Lowering LDL-C levels is important for preventing atherosclerosis, reducing cardiovascular risk, improving endothelial function, and promoting overall cardiovascular health, especially for patients with HoFH Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. This review paper focuses on research findings regarding the therapeutic benefits of lomitapide, highlighting its effectiveness in lowering cholesterol levels and reducing the risk of CVDs The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The oral microbiome is a diverse ecosystem containing a community of symbiotic, commensal, and pathogenic microorganisms. One key microorganism linked to periodontal disease (PD) is Porphyromonas gingivalis ( P. gingivalis ), a Gram-negative anaerobic bacterium known to have several virulence factors that trigger inflammation and immune evasion. On the other hand, Akkermansia muciniphila ( A. muciniphila ), a symbiotic bacterium, has been recently shown to play an important role in mitigating inflammation and reducing periodontal damage. In vivo and in vitro studies have shown that A. muciniphila decreases inflammatory mediators and improves immune responses, suggesting its role in mitigating PD and related inflammatory systemic conditions such as diabetes, hypertension, and obesity. This review discusses the anti-inflammatory effects of A. muciniphila , its impact on periodontal health, and its potential role in managing systemic diseases. The overall aim is to elucidate how this bacterium might help reduce inflammation, improve oral health, and influence broader health outcomes.

Background: The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. We examined whether irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared with long-term administration., Methods and Results: C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy X-ray head-and-neck irradiation. Pravastatin was then administered either for an additional 24 hours or for 1 year. Carotid arteries were tested for vascular reactivity, altered gene expression, and collagen deposition 1 year after irradiation. Treatment with pravastatin for 24 hours after irradiation reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction. Expression of markers associated with inflammation (NFκB p65 [phospho-nuclear factor kappa B p65] and TNF-α [tumor necrosis factor alpha]) and with oxidative stress (NADPH oxidases 2 and 4) were lowered and subunits of the voltage and Ca 2+ activated K + BK channel (potassium calcium-activated channel subfamily M alpha 1 and potassium calcium-activated channel subfamily M regulatory beta subunit 1) in the carotid artery were modulated. Treatment with pravastatin for 1 year after irradiation completely reversed irradiation-induced changes., Conclusions: Short-term administration of pravastatin is sufficient to reduce chronic vascular injury at 1 year after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.

Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process.

Background: The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. However, the mechanisms by which statins protect the vasculature from irradiation injury remain poorly understood., Objectives: Identify the mechanisms by which the hydrophilic and lipophilic statins pravastatin and atorvastatin preserve endothelial function after irradiation., Methods: Cultured human coronary and umbilical vein endothelial cells irradiated with 4 Gy and mice subjected to 12 Gy head-and-neck irradiation were pretreated with statins and tested for endothelial dysfunction, nitric oxide production, oxidative stress, and various mitochondrial phenotypes at 24 and 240 h after irradiation., Results: Both pravastatin (hydrophilic) and atorvastatin (lipophilic) were sufficient to prevent the loss of endothelium-dependent relaxation of arteries after head-and-neck irradiation, preserve the production of nitric oxide by endothelial cells, and suppress the cytosolic reactive oxidative stress associated with irradiation. However, only pravastatin inhibited irradiation-induced production of mitochondrial superoxide; damage to the mitochondrial DNA; loss of electron transport chain activity; and expression of inflammatory markers., Conclusions: Our findings reveal some mechanistic underpinnings of the vasoprotective effects of statins after irradiation. Whereas both pravastatin and atorvastatin can shield from endothelial dysfunction after irradiation, pravastatin additionally suppresses mitochondrial injury and inflammatory responses involving mitochondria. Clinical follow-up studies will be necessary to determine whether hydrophilic statins are more effective than their lipophilic counterparts in reducing the risk of cardiovascular disease in patients undergoing radiation therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Ait-Aissa, Leng, Lindsey, Guo, Juhr, Koval and Grumbach.)

Objectives: Homozygous familial hypercholesteremia (HoFH) is a rare, life-threatening metabolic disease, mainly caused by a mutation in the LDL receptor. If untreated, HoFH causes premature death from acute coronary syndrome. Lomitapide is approved by the FDA as a therapy to lower lipid levels in adult patients with HoFH. Nevertheless, the beneficial effect of lomitapide in HoFH models remains to be defined. In this study, we investigated the effect of lomitapide on cardiovascular function using LDL receptor-knockout mice (LDLr - / - )., Methods: Six-week-old LDLr - / - mice were fed a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. Lomitapide (1 mg/Kg/Day) was given by oral gavage for the last 2 weeks in the HFD group. Body weight and composition, lipid profile, blood glucose, and atherosclerotic plaques were measured. Vascular reactivity and markers for endothelial function were determined in conductance arteries (thoracic aorta) and resistance arteries (mesenteric resistance arteries (MRA)). Cytokine levels were measured by using the Mesoscale discovery V-Plex assays., Results: Body weight (47.5 ± 1.5 vs. 40.3 ± 1.8 g), % of fat mass (41.6 ± 1.9% vs. 31.8 ± 1.7%), blood glucose (215.5 ± 21.9 vs. 142.3 ± 7.7 mg/dL), and lipid levels (cholesterol: 600.9 ± 23.6 vs. 451.7 ± 33.4 mg/dL; LDL/VLDL: 250.6 ± 28.9 vs. 161.1 ± 12.24 mg/dL; TG: 299.5 ± 24.1 vs. 194.1 ± 28.1 mg/dL) were significantly decreased, and the % of lean mass (56.5 ± 1.8% vs. 65.2 ± 2.1%) was significantly increased in the HFD group after lomitapide treatment. The atherosclerotic plaque area also decreased in the thoracic aorta (7.9 ± 0.5% vs. 5.7 ± 0.1%). After treatment with lomitapide, the endothelium function of the thoracic aorta (47.7 ± 6.3% vs. 80.7 ± 3.1%) and mesenteric resistance artery (66.4 ± 4.3% vs. 79.5 ± 4.6%) was improved in the group of LDLr - / - mice on HFD. This was correlated with diminished vascular endoplasmic (ER) reticulum stress, oxidative stress, and inflammation., Conclusions: Treatment with lomitapide improves cardiovascular function and lipid profile and reduces body weight and inflammatory markers in LDLr - / - mice on HFD.

Objectives: Short-chain fatty acids (SCFAs), the main metabolites released from the gut microbiota, are altered during hypertension and obesity. SCFAs play a beneficial role in the cardiovascular system. However, the effect of SCFAs on cerebrovascular endothelial cells is yet to be uncovered. In this study, we use brain endothelial cells to investigate the in vitro effect of SCFAs on heme oxygenase 2 (HO-2) and mitochondrial function after angiotensin II (Ang-II) treatment., Methods: Brain human microvascular endothelial cells were treated with Ang-II (500 nM for 24 h) in the presence and absence of an SCFAs cocktail (1 μM; acetate, propionate, and butyrate) and/or HO-2 inhibitor (SnPP 5 μM). At the end of the treatment, HO-2, endothelial markers (p-eNOS and NO production), inflammatory markers (TNFα, NFκB-p50, and -p65), calcium homeostasis, mitochondrial membrane potential, mitochondrial ROS and H 2 O 2 , and mitochondrial respiration were determined in all groups of treated cells., Key Results: Our data showed that SCFAs rescued HO-2 after Ang-II treatment. Additionally, SCFAs rescued Ang-II-induced eNOS reduction and mitochondrial membrane potential impairment and mitochondrial respiration damage. On the other hand, SCFAs reduced Ang-II-induced inflammation, calcium dysregulation, mitochondrial ROS, and H 2 O 2 . All of the beneficial effects of SCFAs on endothelial cells and mitochondrial function occurred through HO-2., Conclusions: SCFAs treatment restored endothelial cells and mitochondrial function following Ang-II-induced oxidative stress. SCFAs exert these beneficial effects by acting on HO-2. Our results are opening the door for more studies to investigate the effect the of SCFAs/HO-2 axis on hypertension and obesity-induced cerebrovascular diseases.

Telomerase reverse transcriptase (TERT) (catalytic subunit of telomerase) is linked to the development of coronary artery disease (CAD); however, whether the role of nuclear vs. mitchondrial actions of TERT is involved is not determined. Dominant-negative TERT splice variants contribute to decreased mitochondrial integrity and promote elevated reactive oxygen species production. We hypothesize that a decrease in mitochondrial TERT would increase mt DNA damage, promoting a pro-oxidative redox environment. The goal of this study is to define whether mitochondrial TERT is sufficient to maintain nitric oxide as the underlying mechanism of flow-mediated dilation by preserving mt DNA integrity.Immunoblots and quantitative polymerase chain reaction were used to show elevated levels of splice variants α- and β-deletion TERT tissue from subjects with and without CAD. Genetic, pharmacological, and molecular tools were used to manipulate TERT localization. Isolated vessel preparations and fluorescence-based quantification of mt H 2 O 2 and NO showed that reduction of TERT in the nucleus increased flow induced NO and decreased mt H 2 O 2 levels, while prevention of mitochondrial import of TERT augmented pathological effects . Further elevated mt DNA damage was observed in tissue from subjects with CAD and initiation of mt DNA repair mechanisms was sufficient to restore NO-mediated dilation in vessels from patients with CAD. The work presented is the first evidence that catalytically active mitochondrial TERT, independent of its nuclear functions, plays a critical physiological role in preserving NO-mediated vasodilation and the balance of mitochondrial to nuclear TERT is fundamentally altered in states of human disease that are driven by increased expression of dominant negative splice variants., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society.)

Background: Radiation therapy strongly increases the risk of atherosclerotic vascular disease, such as carotid stenosis. Radiation induces DNA damage, in particular in mitochondria, but the upstream and downstream signaling events are poorly understood. The objective of this study was to define such mechanisms., Methods: Endothelial-specific MCU (mitochondrial Ca 2+ uniporter) knockout and C57Bl6/J mice with or without a preinfusion of a mitoTEMPO (mitochondrial reactive oxygen species [ROS] scavenger) were exposed to a single dose of cranial irradiation. 24, and 240 hours postirradiation, vascular reactivity, endothelial function, and mitochondrial integrity were assessed ex vivo and in vitro., Results: In cultured human endothelial cells, irradiation with 4 Gy increased cytosolic Ca 2+ transients and the mitochondrial Ca 2+ concentration ([Ca 2+ ] mt ) and activated MCU. These outcomes correlated with increases in mitochondrial ROS ( mt ROS), loss of NO production, and sustained damage to mitochondrial but not nuclear DNA. Moreover, irradiation impaired activity of the ETC (electron transport chain) and the transcription of ETC subunits encoded by mitochondrial DNA ( mt DNA). Knockdown or pharmacological inhibition of MCU blocked irradiation-induced mt ROS production, mt DNA damage, loss of NO production, and impairment of ETC activity. Similarly, the pretreatment with mitoTEMPO, a scavenger of mt ROS, reduced irradiation-induced Ca 2+ entry, and preserved both the integrity of the mt DNA and the production of NO, suggesting a feed-forward loop involving [Ca 2+ ] m and mt ROS. Enhancement of DNA repair in mitochondria, but not in the nucleus, was sufficient to block prolonged mt ROS elevations and maintain NO production. Consistent with the findings from cultured cells, in C57BL/6J mice, head and neck irradiation decreased endothelium-dependent vasodilation, and mt DNA integrity in the carotid artery after irradiation. These effects were prevented by endothelial knockout of MCU or infusion with mitoTEMPO., Conclusions: Irradiation-induced damage to mt DNA is driven by MCU-dependent Ca 2+ influx and the generation of mt ROS. Such damage leads to reduced transcription of mitochondrial genes and activity of the ETC, promoting sustained mt ROS production that induces endothelial dysfunction. Our findings suggest that targeting MCU and mt ROS might be sufficient to mitigate irradiation-induced vascular disease.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Authors and Editor-in-Chief. Some of the data presented in Figure 6C, F and G of the paper to which this corrigendum relates were reported incorrectly in the published article. After being contacted by the Journal, the authors discovered an unintentional error in how the original data were analyzed that could affect the accuracy of the subsequent analysis. The raw data were incorrectly grouped in the analysis software, thereby altering the comparisons. Therefore the authors wish to retract the paper and corrigendum and will recollect and reanalyze the data appropriately. The authors apologize for any inconvenience., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Authors and Editor-in-Chief. Some of the data presented in Figure 6C, F and G of the above-titled paper were reported incorrectly in the published article. After being contacted by the Journal, the authors discovered an unintentional error in how the original data were analyzed that could affect the accuracy of the subsequent analysis. The raw data were incorrectly grouped in the analysis software, thereby altering the comparisons. Therefore the authors wish to retract the paper and will recollect and reanalyze the data appropriately. The authors apologize for any inconvenience., (Published by Elsevier Inc.)

Objective: In this study, the effect of lomitapide, a microsomal triglyceride transfer protein inhibitor, on the cardiovascular function in obesity was investigated., Methods: Eight-week-old C57BL/6 mice were fed with high-fat diet for 12 weeks in the presence and absence of lomitapide. Lomitapide was administered by gavage (1 mg/kg/d) during the last 2 weeks of high-fat feeding. Body weight, blood glucose, body composition, and lipid profile were determined. Vascular function and endothelial function markers were studied in the aorta and mesenteric resistance arteries., Results: Lomitapide treatment reduced body weight in mice with obesity. Blood glucose, percentage of fat mass, total cholesterol, and low-density lipoprotein levels were significantly reduced, and the percentage of lean mass was significantly increased after lomitapide treatment. The vascular response to sodium nitroprusside in the aorta and mesenteric arteries was similar among groups. However, the vascular response to acetylcholine was improved in the treated group. This was associated with decreased levels of vascular endoplasmic reticulum stress, inflammation, and oxidative stress., Conclusions: Treatment with lomitapide attenuated the increase in body weight in mice with obesity and restored the lipid profile and vascular function. These effects were accompanied by a decrease in inflammation and oxidative stress., (© 2022 The Obesity Society.)

The prevalence of obesity is increasing worldwide, and novel therapeutic strategies such as enhancement of thermogenic pathways in white adipose tissue (WAT) are gaining more attention. The gut/brain axis plays an essential role in promoting the browning of WAT. However, the mechanism by which this axis regulates WAT function is not fully understood. On the other hand, the role of microRNAs (miRNAs) in the control of WAT browning has already been established. Therefore, understanding the communication pathways linking the gut/brain axis and miRNAs might establish a promising intervention for obesity. Our published data showed that microRNA-204 (miR-204), a microRNA that plays an important role in the control of the central nervous system (CNS) and the pathogenesis of obesity, is affected by gut dysbiosis. Therefore, miR-204 could be a key element that controls the browning of WAT by acting as a potential link between the gut microbiota and the brain. In this review, we summarized the current knowledge about communication pathways between the brain, gut, and miR-204 and examined the literature to discuss potential research directions that might lead to a better understanding of the mechanisms underlying the browning of WAT in obesity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Kassan et al.)

There is abundant evidence demonstrating the association between gut dysbiosis and neurogenic diseases such as hypertension. A common characteristic of resistant hypertension is the chronic elevation in sympathetic nervous system (SNS) activity accompanied by increased release of norepinephrine (NE), indicating a neurogenic component that contributes to the development of hypertension. Factors that modulate the sympathetic tone to the cardiovascular system in hypertensive patients are still poorly understood. Research has identified an interaction between the brain and the gut, and this interaction plays a possible role in the mechanism of heart damage-induced hypertension. Data, however, remain scarce, and further study is required to define the role of microbiota in sympathetic neural function and its relationship with heart damage and blood pressure (BP) control. Experimental evidence has pointed toward a bidirectional relationship between alterations in the types of bacteria present in the gut and neurogenic diseases, such as hypertension. Our published data showed that miR-204, a microRNA that plays an important role in the CNS function, is affected by gut dysbiosis. Therefore, miR-204 could be a key element that regulates normal sinus rhythm and neuronal hypertension. In this review, we will shed light on the potential mechanism by which microbiota affects hypothalamic miR-204, which in turn, could hinder the sympathetic nerve drive to the cardiovascular system leading to arrhythmia and hypertension., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Kassan et al.)

Anticancer drugs play an important role in reducing mortality rates and increasing life expectancy in cancer patients. Treatments include monotherapy and/or a combination of radiation therapy, chemotherapy, hormone therapy, or immunotherapy. Despite great advances in drug development, some of these treatments have been shown to induce cardiotoxicity directly affecting heart function and structure, as well as accelerating the development of cardiovascular disease. Such side effects restrict treatment options and can negatively affect disease management. Consequently, when managing cancer patients, it is vital to understand the mechanisms causing cardiotoxicity to better monitor heart function, develop preventative measures against cardiotoxicity, and treat heart failure when it occurs in this patient population. This review discusses the role and mechanism of major chemotherapy agents with principal cardiovascular complications in cancer patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Gabani et al.)

Objective: Coronary artery disease (CAD) is associated with a compensatory switch in mechanism of flow-mediated dilation (FMD) from nitric oxide (NO) to H 2 O 2 . The underlying mechanism responsible for the pathological shift is not well understood, and recent reports directly implicate telomerase and indirectly support a role for autophagy. We hypothesize that autophagy is critical for shear stress-induced release of NO and is a crucial component of for the pathway by which telomerase regulates FMD. Approach and Results: Human left ventricular, atrial, and adipose resistance arterioles were collected for videomicroscopy and immunoblotting. FMD and autophagic flux were measured in arterioles treated with autophagy modulators alone, and in tandem with telomerase-activity modulators. LC3B II/I was higher in left ventricular tissue from patients with CAD compared with non-CAD (2.8±0.2 versus 1.0±0.2-fold change; P <0.05), although p62 was similar between groups. Shear stress increased Lysotracker fluorescence in non-CAD arterioles, with no effect in CAD arterioles. Inhibition of autophagy in non-CAD arterioles induced a switch from NO to H 2 O 2 , while activation of autophagy restored NO-mediated vasodilation in CAD arterioles. In the presence of an autophagy activator, telomerase inhibitor prevented the expected switch (Control: 82±4%; NG-Nitro-l-arginine methyl ester: 36±5%; polyethylene glycol catalase: 80±3). Telomerase activation was unable to restore NO-mediated FMD in the presence of autophagy inhibition in CAD arterioles (control: 72±7%; NG-Nitro-l-arginine methyl ester: 79±7%; polyethylene glycol catalase: 38±9%)., Conclusions: We provide novel evidence that autophagy is responsible for the pathological switch in dilator mechanism in CAD arterioles, demonstrating that autophagy acts downstream of telomerase as a common denominator in determining the mechanism of FMD.

The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.

Damage to the microvascular endothelium is an important part of normal tissue injury after radiation exposure and driven by the production of pro-oxidants. The Ca2+/calmodulin-dependent protein kinase II is present in the mitochondrial matrix (mitoCaMKII) where it regulates Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) and pro-oxidant production. Here, we demonstrate that radiation exposure disrupts endothelial cell barrier integrity in vitro, but can be abrogated by inhibition of mitoCaMKII, MCU, or opening of the mitochondrial transition pore. Scavenging of mitochondrial pro-oxidants with mitoTEMPO before, but not after irradiation, protected barrier function. Furthermore, markers of apoptosis and mitochondrial pro-oxidant production were elevated at 24 h following irradiation and abolished by mitoCaMKII inhibition. Endothelial barrier dysfunction was detected as early as 2 h after irradiation. Despite only mildly impaired mitochondrial respiration, the intracellular ATP levels were significantly reduced 4 h after irradiation and correlated with barrier function. MitoCaMKII inhibition improved intracellular ATP concentrations by increasing glycolysis. Finally, DNA double strand break repair and non-homologous end joining, two major drivers of ATP consumption after irradiation, were greatly increased but not significantly affected by mitoCaMKII inhibition. These findings support the hypothesis that mitoCaMKII activity is linked to mitochondrial pro-oxidant production, reduced ATP production, and loss of endothelial barrier function following irradiation. The inhibition of mitoCaMKII is a promising approach to limiting radiation-induced endothelial injury., (Published by Elsevier Inc.)

Aim: To quantify the mitochondrial structure of ECs in intact arteries vs. cultured cells., Methods and Results: Cre-stop mito-Dendra2 mice, expressing the fluorescent protein Dendra2 in the mitochondrial matrix only, were used to label EC mitochondria using Cre-recombinase under the control of the VE-cadherin promoter. Conduit arteries, resistance arterioles and veins were fixed, mounted on glass slides and fluorescent images were obtained using a laser scanning confocal microscope (ex 488 nm; em 550 nm). ImageJ was used to calculate form factor (FF) and aspect ratio (AR) of the mitochondrial segments. Mitochondrial fragmentation count (MFC) was calculated by counting non-contiguous mitochondrial particles and dividing by the number of pixels which comprise the mitochondrial network. Primary aortic EC cultures (48 h on culture plates) were generated to compare the mitochondrial structure of cultured ECs vs. intact arteries. Aortic segments were also exposed to high glucose overnight (33 mM) ex vivo, and separate groups of mice were either infused with a high-glucose saline solution (300 mM) via tail vein catheter for 1 h or injected with streptozotocin (STZ; 50 mg/kg) to cause hyperglycaemia. Compared with cultured ECs, the mitochondria of ECs from the intact aorta were more fragmented (MFC: 6.4 ± 2.5 vs. 18.6 ± 9.4, respectively; P < 0.05). The mitochondrial segments of ECs within the aorta were more circular in shape (FF: 3.5 ± 0.75 vs. 1.8 ± 0.30, respectively; P < 0.05) and had less branching (AR: 2.9 ± 0.60 vs. 2.0 ± 0.25, respectively; P < 0.05) compared with cultured ECs. Ex vivo exposure of the intact aorta to high glucose overnight caused mitochondrial fission compared with normal glucose conditions (5 mM; MFC: 25.5 ± 11.1 high glucose vs. 11.0 ± 3.6 normal glucose; P < 0.05). Both 1-h infusion of high glucose saline (MFC: 22.4 ± 4.3) and STZ treatment (MFC: 40.3 ± 14.2) caused mitochondrial fission compared with freshly fixed aortas from control mice (MFC: 18.6 ± 9.4; P < 0.05 vs. high-glucose infusion and STZ treatment)., Conclusions: Using a novel mouse model, we were able to, for the first time, obtain high resolution images of EC mitochondrial structure in intact arteries. We reveal the endothelial mitochondrial network is more fragmented in the intact aorta compared with cultured ECs, indicating that mitochondria assume a more elongated and branched phenotype in cell culture., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Over the past three decades, the increasing rates of obesity have led to an alarming obesity epidemic worldwide. Obesity is associated with an increased risk of cardiovascular diseases; thus, it is essential to define the molecular mechanisms by which obesity affects heart function. Individuals with obesity and overweight have shown changes in cardiac structure and function, leading to cardiomyopathy, hypertrophy, atrial fibrillation, and arrhythmia. Autophagy is a highly conserved recycling mechanism that delivers proteins and damaged organelles to lysosomes for degradation. In the hearts of patients and mouse models with obesity, this process is impaired. Furthermore, it has been shown that autophagy flux restoration in obesity models improves cardiac function. Therefore, autophagy may play an important role in mitigating the adverse effects of obesity on the heart. Throughout this review, we will discuss the benefits of autophagy on the heart in obesity and how regulating autophagy might be a therapeutic tool to reduce the risk of obesity-associated cardiovascular diseases., (© 2019 The Obesity Society.)

MiR-204 is expressed in vascular smooth muscle cells (VSMC). However, its role in VSMC contraction is not known. We determined if miR-204 controls VSMC contractility and blood pressure through regulation of sarcoplasmic reticulum (SR) calcium (Ca 2+ ) release. Systolic blood pressure (SBP) and vasoreactivity to VSMC contractile agonists (phenylephrine (PE), thromboxane analogue (U46619), endothelin-1 (ET-1), angiotensin-II (Ang II) and norepinephrine (NE) were compared in aortas and mesenteric resistance arteries (MRA) from miR-204 -/- mice and wildtype mice (WT). There was no difference in basal systolic blood pressure (SBP) between the two genotypes; however, hypertensive response to Ang II was significantly greater in miR-204 -/- mice compared to WT mice. Aortas and MRA of miR-204 -/- mice had heightened contractility to all VSMC agonists. In silico algorithms predicted the type 1 Inositol 1, 4, 5-trisphosphate receptor (IP 3 R1) as a target of miR-204. Aortas and MRA of miR-204 -/- mice had higher expression of IP 3 R1 compared to WT mice. Difference in agonist-induced vasoconstriction between miR-204 -/- and WT mice was abolished with pharmacologic inhibition of IP 3 R1. Furthermore, Ang II-induced aortic IP 3 R1 was greater in miR-204 -/- mice compared to WT mice. In addition, difference in aortic vasoconstriction to VSMC agonists between miR-204 -/- and WT mice persisted after Ang II infusion. Inhibition of miR-204 in VSMC in vitro increased IP 3 R1, and boosted SR Ca 2+ release in response to PE, while overexpression of miR-204 downregulated IP 3 R1. Finally, a sequence-specific nucleotide blocker that targets the miR-204-IP 3 R1 interaction rescued miR-204-induced downregulation of IP 3 R1. We conclude that miR-204 controls VSMC contractility and blood pressure through IP 3 R1-dependent regulation of SR calcium release., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Coronary artery disease (CAD) is a leading cause of death worldwide and frequently associated with mitochondrial dysfunction. Detailed understanding of abnormalities in mitochondrial function that occur in patients with CAD is lacking. We evaluated mitochondrial damage, energy production, and mitochondrial complex activity in human non-CAD and CAD hearts. Fresh and frozen human heart tissue was used. Cell lysate or mitochondria were isolated using standard techniques. Mitochondrial DNA ( mt DNA), NAD + and ATP levels, and mitochondrial oxidative phosphorylation capacity were evaluated. Proteins critical to the regulation of mitochondrial metabolism and function were also evaluated in tissue lysates. PCR analysis revealed an increase in mt DNA lesions and the frequency of mitochondrial common deletion, both established markers for impaired mitochondrial integrity in CAD compared to non-CAD patient samples. NAD + and ATP levels were significantly decreased in CAD subjects compared to Non-CAD (NAD + fold change: non-CAD 1.00 ± 0.17 vs. CAD 0.32 ± 0.12* and ATP fold change: non-CAD 1.00 ± 0.294 vs. CAD 0.01 ± 0.001*; N = 15, P < 0.005). We observed decreased respiration control index in CAD tissue and decreased activity of complexes I, II, and III. Expression of ETC complex subunits and respirasome formation were increased; however, elevations in the de-active form of complex I were observed in CAD. We observed a corresponding increase in glycolytic flux, indicated by a rise in pyruvate kinase and lactate dehydrogenase activity, indicating a compensatory increase in glycolysis for cellular energetics. Together, these results indicate a shift in mitochondrial metabolism from oxidative phosphorylation to glycolysis in human hearts subjects with CAD.

Introduction: Elevated levels of mitochondrial reactive oxygen species (ROS) contribute to the development of numerous cardiovascular diseases. TERT, the catalytic subunit of telomerase, has been shown to translocate to mitochondria to suppress ROS while promoting ATP production. Acute overexpression of TERT increases survival and decreases infarct size in a mouse model of myocardial infarct, while decreased telomerase activity predisposes to mitochondrial defects and heart failure. In the present study, we examined the role of TERT on cardiac structure and function under basal conditions and conditions of acute or prolonged stress in a novel rat model of TERT deficiency. Methods: Cardiac structure and function were evaluated via transthoracic echocardiogram. Langendorff preparations were used to test the effects of acute global ischemia reperfusion injury on cardiac function and infarction. Coronary flow and left ventricular pressure were measured during and after ischemia/reperfusion (I/R). Mitochondrial DNA integrity was measured by PCR and mitochondrial respiration was assessed in isolated mitochondria using an Oxygraph. Angiotensin II infusion was used as an established model of systemic stress. Results: No structural changes (echocardiogram) or coronary flow/left ventricle pressure (isolated hearts) were observed in TERT -/- rats at baseline; however, after I/R, coronary flow was significantly reduced in TERT -/- compared to wild type (WT) rats, while diastolic Left Ventricle Pressure was significantly elevated ( n = 6 in each group; p < 0.05) in the TERT -/- . Interestingly, infarct size was less in TERT -/- rats compared to WT rats, while mitochondrial respiratory control index decreased and mitochondrial DNA lesions increased in TERT -/- compared to WT. Angiotensin II treatment did not alter cardiac structure or function; however, it augmented the infarct size significantly more in TERT -/- compared to the WT. Conclusion: Absence of TERT activity increases susceptibility to stress like cardiac injury. These results suggest a critical role of telomerase in chronic heart disease.

Background and Purpose: NO produces arteriolar flow-induced dilation (FID) in healthy subjects but is replaced by mitochondria-derived hydrogen peroxide (mtH 2 O 2 ) in patients with coronary artery disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH 2 O 2 in human visceral and subcutaneous adipose arterioles., Experimental Approach: Arterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L-NAME) or H 2 O 2 scavenging (Peg-Cat) ± LPA (10 μM, 30 min), ±LPA 1 /LPA 3 receptor antagonist (Ki16425) or LPA 2 receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells., Key Results: FID was inhibited by L-NAME but not Peg-Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg-Cat while L-NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA 1 and LPA 2 but not LPA 3 receptors were detected in arterioles. LPA 1 but not LPA 3 receptor protein was detected by Western blot. Pretreatment of vessels with an LPA 1 /LPA 3 , but not LPA 2 , receptor antagonist prior to LPA preserved NO-mediated dilation., Conclusions and Implications: These findings suggest an LPA 1 receptor-dependent pathway by which LPA increases arteriolar release of mtH 2 O 2 as a mediator of FMD., (© 2018 The British Pharmacological Society.)

A rise in reactive oxygen species (ROS) may contribute to cardiovascular disease by reducing nitric oxide (NO) levels, leading to loss of NO's vasodilator and anti-inflammatory effects. Although primarily studied in larger conduit arteries, excess ROS release and a corresponding loss of NO also occur in smaller resistance arteries of the microcirculation, but the underlying mechanisms and therapeutic targets have not been fully characterized. We examined whether either of the two subunits of telomerase, telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC), affect microvascular ROS production and peak vasodilation at baseline and in response to in vivo administration to angiotensin II (ANG II). We report that genetic loss of TERT [maximal dilation: 52.0 ± 6.1% with vehicle, 60.4 ± 12.9% with N ω -nitro-l-arginine methyl ester (l-NAME), and 32.2 ± 12.2% with polyethylene glycol-catalase (PEG-Cat) ( P < 0.05), means ± SD, n = 9-19] but not TERC [maximal dilation: 79 ± 5% with vehicle, 10.7 ± 9.8% with l-NAME ( P < 0.05), and 86.4 ± 8.4% with PEG-Cat, n = 4-7] promotes flow-induced ROS formation. Moreover, TERT knockout exacerbates the microvascular dysfunction resulting from in vivo ANG II treatment, whereas TERT overexpression is protective [maximal dilation: 88.22 ± 4.6% with vehicle vs. 74.0 ± 7.3% with ANG II (1,000 ng·kg -1 ·min -1 ) ( P = not significant), n = 4]. Therefore, loss of TERT but not TERC may be a key contributor to the elevated microvascular ROS levels and reduced peak dilation observed in several cardiovascular disease pathologies. NEW & NOTEWORTHY This study identifies telomerase reverse transcriptase (TERT) but not telomerase RNA component as a key factor regulating endothelium-dependent dilation in the microcirculation. Loss of TERT activity leads to microvascular dysfunction but not conduit vessel dysfunction in first-generation mice. In contrast, TERT is protective in the microcirculation in the presence of prolonged vascular stress. Understanding the mechanism of how TERT protects against vascular stress represents a novel target for the treatment of vascular disorders.