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Cardiovascular outcome trials on omega-3 fatty acids have generated contradictory results but indicate a dose-dependent beneficial effect of eicosapentaenoic acid (EPA). Beneficial cardiovascular effects of EPA may in addition to triglyceride lowering be mediated through alternative mechanisms of action. In this review, the link between EPA and a resolution of atherosclerotic inflammation is addressed. EPA is a substrate for the enzymatic metabolism into the lipid mediator resolvin E1 (RvE1), which activates the receptor ChemR23 to transduce an active resolution of inflammation. This has been shown to dampen the immune response and provide atheroprotective responses in different models. The intermediate EPA metabolite 18-HEPE emerges as a biomarker of EPA metabolism towards proresolving mediators in observational studies. Genetic variations within the EPA-RvE1-ChemR23 axis affecting the response to EPA may open up for precision medicine to identify responders and non-responders to EPA and fish oil supplementation. In conclusion, activation of the EPA-RvE1-ChemR23 axis towards a resolution of inflammation may contribute to beneficial effects in cardiovascular prevention., Competing Interests: Declaration of Competing Interest The author has received speaker and consultant fees from Amarin and Novartis. The author's institution has received speaker and consultant fees from Amarin, Amgen, Heel, Novartis, and Fresenius Kabi., (Copyright © 2023 The Author. Published by Elsevier Inc. All rights reserved.)

Chronic inflammation in atherosclerosis reflects a failure in the resolution of inflammation. Pro-resolving lipid mediators derived from omega-3 fatty acids reduce the development of atherosclerosis in murine models. The aim of the present study was to decipher the role of the specialized proresolving mediator (SPM) resolvin D2 (RvD2) in atherosclerosis and its signaling through the G-protein coupled receptor (GPR) 18. The ligand and receptor were detected in human coronary arteries in relation to the presence of atherosclerotic lesions and its cellular components. Importantly, RvD2 levels were significantly higher in atherosclerotic compared with healthy human coronary arteries. Furthermore, apolipoprotein E (ApoE) deficient hyperlipidemic mice were treated with either RvD2 or vehicle in the absence and presence of the GPR18 antagonist O-1918. RvD2 significantly reduced atherosclerosis, necrotic core area, and pro-inflammatory macrophage marker expression. RvD2 in addition enhanced macrophage phagocytosis. The beneficial effects of RvD2 were not observed in the presence of O-1918. Taken together, these results provide evidence of atheroprotective pro-resolving signalling through the RvD2-GPR18 axis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×ApoE double-KO background (hGPR32myc×Fpr2-/-×Apoe-/-), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice as compared with Fpr2-/-×Apoe-/- nontransgenic littermates. In a zymosan-induced peritonitis model, the hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice, but not in Fpr2-/-×Apoe-/- nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.

Atherosclerotic plaques prone to rupture may cause acute myocardial infarction (MI) but can also heal without causing an event. Certain common histopathological features, including inflammation, a thin fibrous cap, positive remodelling, a large necrotic core, microcalcification, and plaque haemorrhage are commonly found in plaques causing an acute event. Recent advances in imaging techniques have made it possible to detect not only luminal stenosis and overall coronary atherosclerosis burden but also to identify such adverse plaque characteristics. However, the predictive value of identifying individual adverse atherosclerotic plaques for future events has remained poor. In this Position Paper, the relationship between vulnerable plaque imaging and MI is addressed, mainly for non-invasive assessments but also for invasive imaging of adverse plaques in patients undergoing invasive coronary angiography. Dynamic changes in atherosclerotic plaque development and composition may indicate that an adverse plaque phenotype should be considered at the patient level rather than for individual plaques. Imaging of adverse plaque burden throughout the coronary vascular tree, in combination with biomarkers and biomechanical parameters, therefore holds promise for identifying subjects at increased risk of MI and for guiding medical and invasive treatment., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Omega-3 fatty acids serve as the substrate for the formation of a group of lipid mediators that mediate the resolution of inflammation. The cardiovascular inflammatory response in atherosclerosis and vascular injury is characterized by a failure in the resolution of inflammation, resulting in a chronic inflammatory response. The proresolving lipid mediator resolvin E1 (RvE1) is formed by enzymatic conversion of the omega-3 fatty acid eicosapentaenoic acid (EPA), and signals resolution of inflammation through its receptor ChemR23. Importantly, the resolution of cardiovascular inflammation is an active, multifactorial process that involves modulation of the immune response, direct actions on the vascular wall, as well as close interactions between macrophages and vascular smooth muscle cells. Promoting anti-atherogenic signalling through the stimulation of endogenous resolution of inflammation pathways may provide a novel therapeutic strategy in cardiovascular prevention.

Inflammation is an important driver of atherosclerosis, and the favourable outcomes of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial revealed the large potential of anti-inflammatory drugs for the treatment of cardiovascular disease, especially in patients with a pro-inflammatory constitution. However, the complex immune reactions driving inflammation in the vascular wall in response to an atherosclerotic microenvironment are still being unravelled. Novel insights into the cellular processes driving immunity and inflammation revealed that alterations in intracellular metabolic pathways are strong drivers of survival, growth, and function of immune cells. Therefore, this position paper presents a brief overview of the recent developments in the immunometabolism field, focusing on its role in atherosclerosis. We will also highlight the potential impact of immunometabolic markers and targets in clinical cardiovascular medicine., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.

Dysregulated lipid metabolism induces an inflammatory and immune response leading to atherosclerosis. Conversely, inflammation may alter lipid metabolism. Recent treatment strategies in secondary prevention of atherosclerosis support beneficial effects of both anti-inflammatory and lipid-lowering therapies beyond current targets. There is a controversy about the possibility that anti-inflammatory effects of lipid-lowering therapy may be either independent or not of a decrease in low-density lipoprotein cholesterol. In this Position Paper, we critically interpret and integrate the results obtained in both experimental and clinical studies on anti-inflammatory actions of lipid-lowering therapy and the mechanisms involved. We highlight that: (i) besides decreasing cholesterol through different mechanisms, most lipid-lowering therapies share anti-inflammatory and immunomodulatory properties, and the anti-inflammatory response to lipid-lowering may be relevant to predict the effect of treatment, (ii) using surrogates for both lipid metabolism and inflammation as biomarkers or vascular inflammation imaging in future studies may contribute to a better understanding of the relative importance of different mechanisms of action, and (iii) comparative studies of further lipid lowering, anti-inflammation and a combination of both are crucial to identify effects that are specific or shared for each treatment strategy.

Background: In addition to enhanced proinflammatory signaling, impaired resolution of vascular inflammation plays a key role in atherosclerosis. Proresolving lipid mediators formed through the 12/15 lipoxygenase pathways exert protective effects against murine atherosclerosis. n-3 Polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), serve as the substrate for the formation of lipid mediators, which transduce potent anti-inflammatory and proresolving actions through their cognate G-protein-coupled receptors. The aim of this study was to identify signaling pathways associated with EPA supplementation and lipid mediator formation that mediate atherosclerotic disease progression., Methods: Lipidomic plasma analysis were performed after EPA supplementation in Apoe -/- mice. Erv1/Chemr23 -/- xApoe -/- mice were generated for the evaluation of atherosclerosis, phagocytosis, and oxidized low-density lipoprotein uptake. Histological and mRNA analyses were done on human atherosclerotic lesions., Results: Here, we show that EPA supplementation significantly attenuated atherosclerotic lesion growth induced by Western diet in Apoe -/- mice and was associated with local cardiovascular n-3 enrichment and altered lipoprotein metabolism. Our systematic plasma lipidomic analysis identified the resolvin E1 precursor 18-monohydroxy EPA as a central molecule formed during EPA supplementation. Targeted deletion of the resolvin E1 receptor Erv1/Chemr23 in 2 independent hyperlipidemic murine models was associated with proatherogenic signaling in macrophages, increased oxidized low-density lipoprotein uptake, reduced phagocytosis, and increased atherosclerotic plaque size and necrotic core formation. We also demonstrate that in macrophages the resolvin E1-mediated effects in oxidized low-density lipoprotein uptake and phagocytosis were dependent on Erv1/Chemr23. When analyzing human atherosclerotic specimens, we identified ERV1/ChemR23 expression in a population of macrophages located in the proximity of the necrotic core and demonstrated augmented ERV1/ChemR23 mRNA levels in plaques derived from statin users., Conclusions: This study identifies 18-monohydroxy EPA as a major plasma marker after EPA supplementation and demonstrates that the ERV1/ChemR23 receptor for its downstream mediator resolvin E1 transduces protective effects in atherosclerosis. ERV1/ChemR23 signaling may represent a previously unrecognized therapeutic pathway to reduce atherosclerotic cardiovascular disease.

Aims: Both leukotrienes and neutrophils have been linked to plaque destabilization. Despite being evoked, the role of leukotriene B4 (LTB4) in neutrophil recruitment to plaques and the concomitant effects of these two actors on plaque stability remain to be proven. Since both actors are elicited during endotoxaemia, a condition associated with the risk of cardiovascular events, we investigated whether endotoxaemia promotes LTB4-mediated neutrophil infiltration in plaques and explored the roles of LTB4 and neutrophils in plaque destabilization., Methods and Results: Endotoxaemia induced by repeated peritoneal endotoxin injections at a non-lethal dose (1.5 mg/kg, 5 days) in chow-fed aged Apoe-/- mice (over 45 weeks old) resulted in neutrophil infiltration and activation in plaques. Subsequently to neutrophil invasion, plaques exhibited increased features of vulnerability: reduced collagen content, expanded necrotic cores, and thinned fibrous caps. These plaque features were reproduced by direct deposition of isolated neutrophils onto murine atheromatous carotid arteries in an in vivo assay. In endotoxemic mice, plaques produced increased amounts of LTB4. Genomic or pharmacological impairments of this production reduced neutrophil infiltration, collagenolysis, and apoptosis of smooth muscle cells in plaques of endotoxemic mice. Furthermore, conditioned media of human culprit plaques (CPs) contained more LTB4 than non-CPs and levels of LTB4 correlated to both neutrophil activation markers and endotoxin releases in CPs., Conclusion: These results show that the increased neutrophil recruitment elicited by LTB4 contributes to increase features of plaque destabilization in endotoxemic contexts and point out LTB4 as a potential therapeutic target in atherosclerosis.

Aims: Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl-leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA-related atherosclerosis., Methods and Results: Determinants of the urinary excretion of LTE 4 (U-LTE 4 ) including history of cardiovascular events, polysomnographic and biological parameters were studied in a cohort of 170 OSA patients and 29 controls, and in a subgroup of OSA patients free of cardiovascular event (n = 136). Mechanisms linking IH, the CysLT pathway and atherogenesis were investigated in Apolipoprotein E deficient (ApoE -/- ) mice exposed to 8-week IH. In the whole cohort, U-LTE 4 was independently influenced by age, minimal oxygen saturation, and a history of cardiovascular events, and correlated significantly with intima-media thickness. In the subgroup of OSA patients free of cardiovascular event, increased U-LTE 4 was increased compared to controls and independently related to hypoxia severity and traditional risk factors aggregated in the 10-year cardiovascular risk score of European Society of Cardiology. In IH mice, atherosclerosis lesion size and mRNA levels of 5-lipoxygenase, 5-lipoxygenase activating protein (FLAP) and CysLT 1 receptor were significantly increased. This transcriptional activation was associated with the binding of HIF-1 to the FLAP promoter and was strongly associated with atherosclerosis lesion size. CysLT 1 receptor antagonism (montelukast) significantly reduced atherosclerosis progression in IH mice., Conclusions: IH-related CysLT pathway activation contributes to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE 4 may be a useful biomarker to identify OSA patients for whom CysLT 1 blockade could represent a new therapeutic avenue for reducing cardiovascular risk., (Copyright © 2018. Published by Elsevier Ltd.)

Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1β blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels >2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1β activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1β blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1β blockade. In addition, IL-1β blockade has only been studied in patients with C-reactive protein >2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1β pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1β blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis.

Background and Purpose: Atherosclerosis is characterized by a chronic non-resolving inflammation in the arterial wall. Aspirin-triggered lipoxin A4 (ATL) is a potent anti-inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE -/- ) mice., Experimental Approach: ApoE -/-  × Fpr2 +/+ and ApoE -/-  × Fpr2 -/- mice were generated. Four-week-old mice fed a high-fat diet for 4 weeks and 16-week-old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4 weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen., Key Results: ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE -/- mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL-induced athero-protection was absent in ApoE -/- mice lacking the Fpr2 receptor., Conclusion and Implications: ATL blocked atherosclerosis progression by means of an Fpr2-mediated reduced local and systemic inflammation. These results suggest this anti-inflammatory and pro-resolving agent has therapeutic potential for the treatment of atherosclerosis., Linked Articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc., (© 2017 The British Pharmacological Society.)

Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging -omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma-derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk prediction., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Leukotriene B4 (LTB4) induces proinflammatory signaling through BLT receptors expressed in atherosclerotic lesions. Either genetic or pharmacological targeting of the high affinity LTB4 receptor, BLT1, reduces atherosclerosis in different mouse models. The low affinity BLT2 receptor for LTB4 may transduce additional pro-atherogenic signaling, but combined BLT1 and BLT2 receptor antagonism has not previously been explored in atherosclerosis. The aim of the present study was to unravel the effects of the BLT receptor antagonist BIIL284 in apolipoprotein E deficient mice in terms of atherosclerotic lesion size and composition, as well as on arterial matrixmetalloproteinase (MMP) activity and plasma cytokines. Oral administration of BIIL284 (0.3-3mg/kg) dose-dependently decreased atherosclerotic lesion size after 12 weeks. In addition, significantly smaller aortic lesions were observed in mice treated with BIIL284 (3mg/kg) for 24 weeks. The reduced atherosclerosis was associated with less lesion smooth muscle cells, less arterial MMP activities and lower plasma levels of TNF-α and IL-6. Taken together, these results suggest a therapeutic value of BLT receptor antagonism in atherosclerosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of low-density lipoprotein in the artery, leading to maladaptive response of cells from the immune system and vessel wall. Strong evidence implicates indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the kynurenine pathway of tryptophan (Trp) degradation, with immune regulation and anti-inflammatory mechanisms in different diseases. However, the role of IDO and the endogenous degradation of Trp have never been directly examined in atherosclerosis development. We used the IDO inhibitor 1-methyl-Trp (1-MT) to determine the role of IDO-mediated Trp metabolism in vascular inflammation and atherosclerosis., Methods and Results: Apoe(-/-) mice were treated with 1-MT in drinking water for 8 weeks. Systemic IDO inhibition led to a significant increase in atherosclerotic lesions that were ∼58 and 54% larger in the aortic arch and root, respectively. 1-MT treatment enhanced vascular inflammation, up-regulated VCAM-1 and CCL2, and increased CD68 macrophage accumulation into the plaque. Notably, the rise in VCAM-1 expression was not limited to the plaque but also found in smooth muscle cells (SMCs) of the tunica media. Furthermore, we found that IDO-dependent Trp metabolism by SMCs regulates VCAM-1 expression, and that 1-MT-induced acceleration of atherosclerosis and vascular inflammation can be reversed by exogenous administration of the Trp metabolite 3-hydroxyanthranilic acid (3-HAA)., Conclusion: IDO-mediated Trp metabolism regulates vascular inflammation and plaque formation in hypercholesterolaemic Apoe(-/-) mice. Our data establish that this pathway plays a major role in the pathological process of atherogenesis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

The view of atherosclerosis as an inflammatory disease has emerged from observations of immune activation and inflammatory signalling in human atherosclerotic lesions, from the definition of inflammatory biomarkers as independent risk factors for cardiovascular events, and from evidence of low-density lipoprotein-induced immune activation. Studies in animal models of hyperlipidaemia have also supported the beneficial effects of countering inflammation to delay atherosclerosis progression. Specific inflammatory pathways with relevance to human diseases have been identified, and inhibitors of these pathways are either already in use for the treatment of other diseases, or are under development and evaluation. These include 'classic' drugs (such as allopurinol, colchicine, and methotrexate), biologic therapies (for example tumour necrosis factor inhibitors and IL-1 neutralization), as well as targeting of lipid mediators (such as phospholipase inhibitors and antileukotrienes) or intracellular pathways (inhibition of NADPH oxidase, p38 mitogen-activated protein kinase, or phosphodiesterase). The evidence supporting the use of anti-inflammatory therapies for atherosclerosis is mainly based on either observational or small interventional studies evaluating surrogate markers of disease activity. Nevertheless, these data are crucial to understand the role of inflammation in atherosclerosis, and to design randomized controlled studies to evaluate the effect of specific anti-inflammatory strategies on cardiovascular outcomes.

Aims: The formyl peptide receptor (FPR) subtype FPR2/ALX transduces pro-inflammatory responses and participates in the resolution of inflammation depending on activation. The aim of the present study was to unravel the role of FPR2/ALX signalling in atherosclerosis., Methods and Results: Expression of FPR2/ALX was analysed in 127 human carotid atherosclerotic lesions and revealed that this receptor was expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Furthermore, FPR2/ALX mRNA levels were significantly up-regulated in atherosclerotic lesions compared with healthy vessels. In multiple regression, age, creatinine, and clinical signs of increased cerebral ischaemia were independent predictors of FPR2/ALX expression. To provide mechanistic insights into these observations, we generated Ldlr(-/-)xFpr2(-/-) mice, which exhibited delayed atherosclerosis development and less macrophage infiltration compared with Ldlr(-/-)xFpr2(+/+) mice. These findings were reproduced by transplantation of Fpr2(-/-) bone marrow into Ldlr(-/-) mice and further extended by in vitro experiments, demonstrating a lower inflammatory state in Fpr2(-/-) macrophages. FPR2/ALX expression correlated with chemo- and cytokines in human atherosclerotic lesions and leucocytes. Finally, atherosclerotic lesions in Ldlr(-/-)xFpr2(-/-) mice exhibited decreased collagen content, and Fpr2(-/-) SMCs exhibited a profile of increased collagenase and decreased collagen production pathways., Conclusion: FPR2/ALX is proatherogenic due to effects on bone marrow-derived cells, but promoted a more stable plaque phenotype through effects on SMCs. Taken together, these results suggest a dual role of FPR2/ALX signalling in atherosclerosis by way of promoting disease progression and but increasing plaque stability., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Blood vessels are exposed to multiple mechanical forces that are exerted on the vessel wall (radial, circumferential and longitudinal forces) or on the endothelial surface (shear stress). The stresses and strains experienced by arteries influence the initiation of atherosclerotic lesions, which develop at regions of arteries that are exposed to complex blood flow. In addition, plaque progression and eventually plaque rupture is influenced by a complex interaction between biological and mechanical factors-mechanical forces regulate the cellular and molecular composition of plaques and, conversely, the composition of plaques determines their ability to withstand mechanical load. A deeper understanding of these interactions is essential for designing new therapeutic strategies to prevent lesion development and promote plaque stabilization. Moreover, integrating clinical imaging techniques with finite element modelling techniques allows for detailed examination of local morphological and biomechanical characteristics of atherosclerotic lesions that may be of help in prediction of future events. In this ESC Position Paper on biomechanical factors in atherosclerosis, we summarize the current 'state of the art' on the interface between mechanical forces and atherosclerotic plaque biology and identify potential clinical applications and key questions for future research., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

The n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), displays anti-inflammatory properties that may prevent atherosclerosis progression. Exposure of apolipoprotein-E deficient (ApoE(-/-)) mice to chronic intermittent hypoxia (CIH) accelerates atherosclerosis progression. Our aim was to assess DHA-supplementation influence on fatty acid incorporation in different tissues/organs and on atherosclerosis progression in ApoE(-/-) mice exposed to CIH. ApoE(-/-) mice were exposed to CIH or normoxia (N) and randomized to four groups (N control, CIH control, N+DHA, and CIH+DHA). DHA-supplementation enhanced DHA and reduced arachidonic acid (AA) contents in tissues/organs. CIH control mice exhibited increased atherosclerosis lesion sizes compared to N control mice. DHA prevented CIH induced atherosclerosis but did not improve atherosclerosis burden in N mice. Aortic matrix metalloproteinase-2 (MMP-2) expression was decreased in CIH+DHA mice (p=0.007). DHA-supplementation prevented CIH-induced atherosclerosis acceleration. This was associated with a decrease of AA incorporation and of aortic MMP-2 gene expression., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Leukotrienes are biologically active lipid mediators of inflammation involved in atherogenesis. Obstructive sleep apnoea (OSA) patients exhibit early atherosclerosis and activation of the leukotriene pathway. In OSA patients, the production of leukotrienes is increased in relation to OSA severity and in vitro exposure of immune cells to intermittent hypoxia increases leukotriene pathway transcription. Moreover, the leukotriene transcriptional pathway is associated with early vascular remodelling. Lastly, obesity is a major confounding factor for leukotriene activation in OSA. The aim of this review was to focus on the intricate network of leukotrienes, chronic intermittent hypoxia, and atherosclerosis, with an emphasis on the role of leukotrienes in the early atherosclerosis observed in OSA patients.

Objective: Whereas circulating levels of C-reactive protein (CRP) have been associated with, for example, arterial stiffness, subclinical atherosclerosis and metabolic syndrome, other inflammatory biomarkers with potential interest for these conditions may not be measurable systemically. The predictive value of salivary biomarkers in these contexts has remained largely unexplored. The aim of the present study was to establish the association of different salivary biomarkers of inflammation with subclinical cardiovascular disease., Methods: Two hundred and fifty-nine individuals were included in the study. Saliva and plasma samples were collected, and each individual underwent carotid ultrasound and measures of pulse wave velocity and blood pressure. Medical history of previous cardiovascular disease, current medications and smoking were collected by questionnaire., Results: Salivary levels of CRP, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), matrix metalloproteinase 9 (MMP-9), creatinine and lysozyme were measured. Salivary levels of CRP were significantly correlated with plasma levels (r = 0.73, P < 0.0001). In an age-adjusted and sex-adjusted analysis, salivary CRP was significantly and positively correlated with mean arterial blood pressure, pulse pressure, pulse wave velocity, BMI, metabolic syndrome, waist-to-hip ratio and intima-media thickness. Increasing age and sex-adjusted salivary CRP tertiles were in addition associated with carotid plaques. In a multivariate analysis, CRP and MMP-9 were associated with intima-media thickness, LTB4 and PGE2 with arterial stiffness, and lysozyme with hypertension., Conclusion: Saliva may represent an alternative mean for evaluation of cardiovascular risk.

Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E(-/-) mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p<0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.

Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A(2), are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A(2)) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional antagonists., (© 2012 Wiley Periodicals, Inc.)

Leukotriene B(4) (LTB(4)) production increases in obstructive sleep apnea syndrome (OSA) and is linked to early vascular remodeling, the mechanism of which is unknown. The objective of this study was to to determine the molecular mechanisms of LTB(4) pathway activation in polymorphonuclear cells (PMNs) and early vascular remodeling in OSA and the specific contribution of intermittent hypoxia (IH). PMNs were isolated from 120 OSA patients and 33 healthy subjects and used for measurements of LTB(4) production, determination of mRNA and protein expression levels, or exposed for four cycles of in vitro IH. PMNs derived from OSA patients exhibited increased LTB(4) production, for which apnea-hypopnea index was an independent predictor (P=0.042). 5-Lipoxygenase-activating protein (FLAP) mRNA and protein increased significantly in PMNs from OSA patients versus controls and were associated with carotid luminal diameter and intima-media thickness. LTB(4) (10 ng/ml) increased IL-6 (P=0.006) and MCP-1 (P=0.002) production in OSA patient monocytes. In vitro exposure of PMNs from controls to IH enhanced FLAP mRNA levels (P= 0.027) and induced a 2.7-fold increase (P=0.028) in LTB(4) secretion compared with PMNs exposed to normoxia. In conclusion, upregulation of FLAP in PMNs in response to IH may participate in early vascular remodeling in OSA patients, suggesting FLAP as a potential therapeutic target for the cardiovascular morbidity associated with OSA.

Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical atherosclerosis at this stage misses a major opportunity to prevent the long-term consequences of this disease. Surrogate biological and structural vascular markers are available to determine the presence and the extension of preclinical vascular injury in the general population. Examples of surrogate markers are carotid intima media thickness and biomarkers including high-sensitivity C-reactive protein, cell adhesion molecules and matrix metalloproteinases, and leukotrienes. Recently, leukotrienes have been implicated as mediators, biomarkers, and possible therapeutic targets in the context of subclinical atherosclerosis. The aim of this short paper is to focus on the relation between preclinical atherosclerosis and leukotrienes, with particular attention to the recent development on the use of leukotriene modifiers in the treatment of atherosclerosis.

The matrix metalloproteinase (MMP) family of enzymes is involved in arterial wall extracellular matrix degradation and remodeling. The latter activities have been implicated in a number of normal and pathologic processes, such as atherosclerotic lesion formation and progression, plaque destabilization and rupture, but also in plaque stabilization and healing. As a result, the MMPs have been explored as both therapeutic targets and diagnostic tools for the treatment and diagnosis of atherosclerotic cardiovascular diseases. In this review, we summarize experimental findings, genetic associations, and the biomarker potential of MMPs in atherothrombosis. In addition, the regulation and expression of MMPs in atherosclerotic plaques is discussed, with an emphasis on the role of lipid-derived inflammatory mediators as modulators of MMP activity.

Thromboxane A(2) (TXA(2)) is a potent prothrombotic and immune modulating lipid mediator, which is implicated in cardiovascular diseases, in particular, atherosclerotic lesion development and thrombogenicity. Here, we tested the hypothesis that thromboxane synthase (TXAS), the obligate enzyme required to synthesize TXA(2), is expressed within the human atherosclerotic lesion, thus potentially contributing to TXA(2) synthesis and disease development. In an animal study, different atherosclerosis-prone mouse strains were investigated and compared with control mice. In a patient study (n = 134), endarterectomies of carotid atherosclerotic lesions were compared with non-atherosclerotic arteries (n = 11). Expression of TXAS was evaluated by real-time quantitative reverse transcription PCR and immunohistochemistry. TXAS mRNA expression was increased within the vascular wall in mouse models of atherosclerosis with advanced lesions. In humans, TXAS was expressed in the atherosclerotic lesion, associated with increased inflammatory cells, in particular M2 polarized macrophages, and increased in atherosclerotic lesions of patients with recent symptoms of thrombotic events. Production of TXA(2) by plaque tissue, verified by gas chromatography-mass spectrometry, increased after addition of arachidonic acid or lipopolysaccharide, and was inhibited by the TXAS inhibitor furegrelate. The findings suggest that intraplaque TXA(2) generation may contribute to the development of atherosclerosis and its thrombotic complications in humans.

Evidence from experimental and genetic studies suggest the existence of a potential link between the leukotrienes (LT) signalling cascade, and the pathogenesis/progression of atherosclerosis and its serious consequences such as acute myocardial infarction (AMI), stroke, aortic aneurysms, and intimal hyperplasia. LT biosynthetic enzymes are expressed within atherosclerotic lesion, leading to production of cysteinyl-leukotrienes (Cys-LTs) and LTB4 that exert potent pro-inflammatory action through interaction with CysLT and BLT receptor subtypes expressed on inflammatory and structural cells within the vascular wall. Genetic variants in the genes of the 5-LO pathway have been associated with the risk of developing AMI and stroke. As a result, anti-LT have recently received renewed interest for the treatment of atherosclerosis and its ischemic complications. The aim of this short review is to summarize our current understanding of the role of LTs and their receptors in the genesis and progression of atherosclerosis and review the recent developments on the use of antagonists.

The metalloproteinases (MMPs, matrixins) are zinc-containing endopeptidases involved in the metabolism of extracellular matrix as well as in the cleavage of other proteins. The MMP family currently consists of 28 enzymes with somewhat different activities. The members are in part categorized into groups according to either structure or preferred substrates and referred to as collagenases, gelatinases, stromelysins, matrilysins, and membrane-bound MMPs. The proteinase activities exerted by 11 of the 28 MMPs have been implicated in some of the biologic processes associated with atherosclerosis and its ischemic clinical manifestations such as myocardial infarction and stroke. For example, several of the MMPs are locally expressed within human atherosclerotic lesions. However, association studies of subclinical atherosclerosis have generated contradictory results in the role of MMP activities. In addition, circulating MMP levels as well as genetic variations within the genes encoding the different enzymes have been associated with both an increased and decreased cardiovascular risk. Finally, experimental studies of hyperlipemic mice and vascular injury have suggested some of the MMPs function as modulators of atherogenesis, vascular remodeling, and plaque rupture., (Copyright 2010 Elsevier Inc. All rights reserved.)

Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 micromol/l) and indomethacin (1.7 micromol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I(2) but not of prostaglandin E(2), prostaglandin D(2), or thromboxane A(2) in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I(2) release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.

Introduction: The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by phospholipase A(2) serves as substrate for the production of a group of lipid mediators known as the leukotrienes, which induce pro-inflammatory signaling through activation of specific BLT and CysLT receptors., Discussion: Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Finally, studies of either myocardial or cerebral ischemia and reperfusion indicate that leukotriene signaling in addition may be involved in the development of ischemic injury., Conclusion: Both leukotriene synthesis inhibitors and leukotriene receptor antagonists have been suggested to induce beneficial effects at different stages of the atherosclerosis process.

The inflammatory environment within the atherosclerotic lesion stimulates the 5-lipoxygenase pathway of arachidonic acid metabolism, leading to the biosynthesis of the potent lipid inflammatory mediators leukotrienes. The present review summarizes the components of this pathway; the enzymes 5-lipoxygenase (5-LO, ALOX5) with its activating protein, FLAP (ALOX5AP), LTA(4) hydrolase and LTC(4) synthase, as well as the receptors for leukotriene B(4) (BLT(1) and BLT(2)) and cysteinyl-leukotrienes (CysLT(1) and CysLT(2)), respectively. Genetic variations within the genes encoding these proteins have been associated with cardiovascular risk. Inhibiting the 5-lipoxygenase pathway through either leukotriene synthesis inhibitors or leukotriene receptor antagonists in experimental models of atherosclerosis has however generated contradictory results. Several inhibitors of the 5-lipoxygenase pathway are now evaluated in clinical trials of patients with cardiovascular disease.

The atherosclerotic lesion is a site of local production of the lipid-derived inflammatory mediators known as leukotrienes. This production leads to autocrine and paracrine activation of leukotriene receptors of the BLT and CysLT receptor subtypes expressed on leukocytes and structural cells within the vascular wall. Studies in mice, rats, and rabbits have revealed a key role for leukotriene signaling in atherosclerosis, abdominal aneurysms, and intimal hyperplasia. In addition, a major atherosclerotic immune activation may be leukotriene-dependent through mediation of leukocyte cross-talk within the atherosclerotic lesion. Furthermore, leukotrienes induce endothelium-dependent and independent vascular responses. Finally, recent findings indicate that leukotriene-dependent degradation of the extracellular matrix may link this pathway to atherosclerotic plaque instability. Taken together, the leukotriene pathway may represent a putative therapeutic target in the treatment of atherosclerotic vessel disease.

Recent studies indicate that periodontal disease is associated with the development of early atherosclerotic lesions in the carotid artery. Since inflammation is a key feature in both atherosclerosis and periodontal disease, a common mediator of the two diseases could be anticipated. Leukotrienes are lipid-derived inflammatory mediators recently implicated in the pathogenesis of atherosclerosis and previously shown to be produced in periodontitis. The aim of the present study was to detect leukotrienes in gingival crevicular fluid (GCF) from subjects with atherosclerosis. Carotid ultrasonography and oral clinical examination were performed in 19 periodontitis patients and 16 healthy subjects. Atherosclerotic plaques were detected on ultrasound examination in 13 subjects with periodontis, and in 5 of the healthy subjects. Elevated concentrations of leukotriene B(4) and cysteinyl-leukotrienes were detected in GCF from subjects with a high dental plaque index (PLI>0.3), supporting an increased leukotriene formation in periodontitis. In addition, subjects with atherosclerotic plaques had significantly elevated concentrations of cysteinyl-leukotrienes in their GCF as compared with subjects without a visible plaque. Finally, the increased cysteinyl-leukotriene concentrations in GCF from atherosclerotic subjects were observed also when sub groups of periodontis patients and healthy subjects were compared separately. In summary, increased GCF concentrations of cysteinyl-leukotrienes were correlated to measures of both periodontitis and atherosclerosis. These results suggest that increased leukotriene formation may represent a possible link between periodontitis and atherosclerosis and a risk factor marker for both diseases.

Transforming growth factor-beta (TGF-beta) is a major antiinflammatory mediator in atherosclerosis. Transgenic ApoE(-/-) mice with a dominant-negative TGFbeta type II receptor (dnTGFbetaRII) on CD4(+) and CD8(+) T cells display aggravated atherosclerosis. The aim of the present study was to elucidate the mechanisms involved in this enhanced inflammatory response. Gene array analyses identified the 5-lipoxygenase-activating protein (FLAP) among the most upregulated genes in both the aorta and adipose tissue of dnTGFbetaRII transgenic ApoE(-/-) mice compared with their ApoE(-/-) littermates, a finding that was confirmed by real-time quantitative RT-PCR. Aortas from the former mice in addition produced increased amounts of the lipoxygenase product leukotriene B(4) after ex vivo stimulation. FLAP protein expression in both the aorta and adipose tissue was detected in macrophages, but not in T cells. Four weeks of treatment with the FLAP inhibitor MK-886 (10 mg/kg in 1% tylose delivered by osmotic pumps) significantly reduced atherosclerotic lesion size and T-cell content. Finally, FLAP mRNA levels were upregulated approximately 8-fold in adipose tissue derived from obese ob/ob mice. In conclusion, the results of the present study suggest a key role for mediators of the 5-lipoxygenase pathway in inflammatory reactions of atherosclerosis and metabolic disease.

Leukotriene-forming enzymes are expressed within atherosclerotic lesions and locally produced leukotrienes exert pro-inflammatory actions within the vascular wall by means of cell surface receptors of the BLT and CysLT receptor subtypes. The migration and accumulation of inflammatory cells that follow leukotriene receptor activation have been implicated in atherosclerosis initiation and progression. Leukotriene receptors are in addition expressed on endothelial and vascular smooth muscle cells, associated with intimal hyperplasia in early atherosclerosis and restenotic lesions after angioplasty. Taken together, recent evidence suggests that leukotriene receptors may be a potential target in the treatment of atherosclerosis and in the prevention of restenosis after coronary interventions.

Leukotriene B(4) (LTB(4)), a potent leukocyte chemoattractant derived from the 5-lipoxygenase metabolism of arachidonic acid, exerts its action by means of specific cell surface receptors, denoted BLT(1) and BLT(2). In this study, BLT(1) receptor proteins were detected in human carotid artery atherosclerotic plaques, colocalizing with markers for macrophages, endothelial cells, and vascular smooth muscle cells (SMC). Challenge of human coronary artery SMC with either LTB(4) or U75302, a partial agonist that is selective for the BLT(1) receptor, induced an approximately 4-fold increase of whole-cell currents by using the patch-clamp technique, indicating that these cells express functional BLT(1) receptors. LTB(4) induced migration and proliferation of SMC in vitro, and treatment with the BLT receptor antagonist BIIL 284 (10 mg/kg, once daily) for 14 days after carotid artery balloon injury in vivo inhibited intimal hyperplasia in rats. In the latter model, SMC derived from the intima exhibited increased levels of BLT(1) receptor mRNA compared with medial SMC. BLT receptor up-regulation in the intima in vivo, as well as that induced by IL-1beta in vitro, were prevented by transfection with a dominant-negative form of Ikappa kinase beta carried by adenovirus, indicating that BLT(1) receptor expression depends on NF-kappaBeta. These results show that LTB(4) activates functional BLT(1) receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT(1) receptors were up-regulated through an Ikappa kinase beta/NF-kappaB-dependent pathway. Inhibition of LTB(4)/BLT(1) signaling during the response to vascular injury reduced intimal hyperplasia, suggesting this pathway as a possible target for therapy.

The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD. [ABSTRACT FROM AUTHOR]

Calcification of the arterial wall and valves is an important part of the pathophysiological process of peripheral and coronary atherosclerosis, aortic stenosis, ageing, diabetes, and chronic kidney disease. This review aims to better understand how extracellular phosphates and their ability to be retained as calcium phosphates on the extracellular matrix initiate the mineralization process of arteries and valves. In this context, the physiological process of bone mineralization remains a human model for pathological soft tissue mineralization. Soluble (ionized) calcium precipitation occurs on extracellular phosphates; either with inorganic or on exposed organic phosphates. Organic phosphates are classified as either structural (phospholipids, nucleic acids) or energetic (corresponding to phosphoryl transfer activities). Extracellular phosphates promote a phenotypic shift in vascular smooth muscle and valvular interstitial cells towards an osteoblast gene expression pattern, which provokes the active phase of mineralization. A line of defense systems protects arterial and valvular tissue calcifications. Given the major roles of phosphate in soft tissue calcification, phosphate mimetics, and/or prevention of phosphate dissipation represent novel potential therapeutic approaches for arterial and valvular calcification. [ABSTRACT FROM AUTHOR]

Background and Purpose: Atherosclerosis is characterized by a chronic non-resolving inflammation in the arterial wall. Aspirin-triggered lipoxin A4 (ATL) is a potent anti-inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE-/- ) mice.Experimental Approach: ApoE-/-  × Fpr2+/+ and ApoE-/-  × Fpr2-/- mice were generated. Four-week-old mice fed a high-fat diet for 4 weeks and 16-week-old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4 weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen.Key Results: ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE-/- mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL-induced athero-protection was absent in ApoE-/- mice lacking the Fpr2 receptor.Conclusion and Implications: ATL blocked atherosclerosis progression by means of an Fpr2-mediated reduced local and systemic inflammation. These results suggest this anti-inflammatory and pro-resolving agent has therapeutic potential for the treatment of atherosclerosis.Linked Articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc. [ABSTRACT FROM AUTHOR]

Although a high marine food intake is considered cardioprotective, randomized trials of ω-3 fatty acids initially generated conflicting results in terms of the role of ω-3 supplementation in cardiovascular prevention. This work demonstrates the results of the 3 most recent clinical trials with ω-3 fatty acids are put into the context of possible mechanisms mediating their beneficial cardiovascular effects. In particular, the randomized Reduction of Cardiovascular Events with EPA Intervention Trial (REDUCE-IT) showed that icosapent ethyl, which is the ethyl ester form of the ω-3 fatty acid eicosapentaenoic acid (EPA), induced a significant reduction of cardiovascular events. Importantly, EPA serves as a substrate for the formation of the specialized proresolving mediator resolvin E1 (RvE1), which stimulates the resolution of inflammation. RvE1 reduces atherosclerosis and intimal hyperplasia by means of its specific receptor ERV1/ChemR23. The decreased levels of proinflammatory and proatherosclerotic leukotrienes by ω-3 fatty acids may further contribute to a beneficial inflammatory balance. Consequently, the Rv/leukotriene ratio is emerging as a marker of nonresolving vascular inflammation. Recent experimental studies have shown that anti-inflammatory and proresolving effects of lipid mediators derived from ω-3 fatty acids inhibit atherosclerosis independently of cholesterol and triglyceride levels. The results of the 3 most recent clinical trials of ω-3 fatty acid supplementation indicate an importance of the type and dose of ω-3 supplementation and highlight the need for risk stratification in the patient selection for ω-3 supplementation for either primary or secondary prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]