Peripartum cardiomyopathy- can the link between prolactin and PAI-1 provide a clue?

© 2020 Oxford University Press. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The version of record, Diana A Gorog, Gemma Vilahur, Peripartum cardiomyopathy: can the link between prolactin and PAI-1 provide a clue?, Cardiovascular Research, cvaa109, is available online at: https://doi.org/10.1093/cvr/cvaa109.Peer reviewe

Atherosclerosis and Thrombosis: Insights from Large Animal Models

Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. The combination of in vitro, ex vivo, and in vivo experimental approaches has largely contributed to a better understanding of the mechanisms underlying the atherothrombotic process. Indeed, different animal models have been implemented in atherosclerosis and thrombosis research in order to provide new insights into the mechanisms that have already been outlined in isolated cells and protein studies. Yet, although no model completely mimics the human pathology, large animal models have demonstrated better suitability for translation to humans. Indeed, direct translation from mice to humans should be taken with caution because of the well-reported species-related differences. This paper provides an overview of the available atherothrombotic-like animal models, with a particular focus on large animal models of thrombosis and atherosclerosis, and examines their applicability for translational research purposes as well as highlights species-related differences with humans

Novel Antithrombotic Agents in Ischemic Cardiovascular Disease : Progress in the Search for the Optimal Treatment

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER) A way of making Europe; Sociedad Española de Cardiología (SEC/FEC-INV-TRL 20/015); Fundación Investigación Cardiovascular-Fundación Jesus Serra.Ischemic cardiovascular diseases have a high incidence and high mortality worldwide. Therapeutic advances in the last decades have reduced cardiovascular mortality, with antithrombotic therapy being the cornerstone of medical treatment. Yet, currently used antithrombotic agents carry an inherent risk of bleeding associated with adverse cardiovascular outcomes and mortality. Advances in understanding the pathophysiology of thrombus formation have led to the discovery of new targets and the development of new anticoagulants and antiplatelet agents aimed at preventing thrombus stabilization and growth while preserving hemostasis. In the following review, we will comment on the key limitation of the currently used antithrombotic regimes in ischemic heart disease and ischemic stroke and provide an in-depth and state-of-the-art overview of the emerging anticoagulant and antiplatelet agents in the pipeline with the potential to improve clinical outcomes

La teràpia antiplaquetar : clau per al tractament de l'aterotrombosis coronària

El futur en el tractament de la isquèmia coronària i de la seva patologia més perillosa, l'aterotrombosis, dependrà de les millores en la investigació. Enfront d'una malaltia de la qual encara es desconeix el tractament definitiu, la detecció i control de les plaques d'ateroma en les artèries és el primer pas, i el més important. Per això, potenciar els medicaments en ús i descobrir agents alternatius dintre dels esquemes antiplaquetaris que ja estan marcats, podrà donar llum al tractament d'una afecció que ja és la responsable del major nombre de morts prematures de l'home actual

Unraveling the complexity of hdl remodeling : On the hunt to restore hdl quality

Altres ajuts: European Regional Development Fund (FEDER)Increasing evidence has cast doubt over the HDL-cholesterol hypothesis. The complexity of the HDL particle and its proven susceptibility to remodel has paved the way for intense molecular investigation. This state-of-the-art review discusses the molecular changes in HDL particles that help to explain the failure of large clinical trials intending to interfere with HDL metabolism, and details the chemical modifications and compositional changes in HDL-forming components, as well as miRNA cargo, that render HDL particles ineffective. Finally, the paper discusses the challenges that need to be overcome to shed a light of hope on HDL-targeted approaches

Network-Assisted Systems Biology Analysis of the Mitochondrial Proteome in a Pre-Clinical Model of Ischemia, Revascularization and Post-Conditioning

Altres ajuts: Ministerio de Ciencia e Innovación; Fundación de Investigación Cardiovascular-Fundación Jesús Serra.Infarct size is the major risk predictor for developing heart failure after an acute myocardial infarction (AMI). The discovery of the conditioning phenomena (i.e., repetitive brief cycles of ischemia applied either before or after a prolonged ischemic insult) has highlighted the existence of endogenous protective mechanisms of the heart potentially limiting infarct size after revascularization. However, most cardioprotective strategies, aiming at infarct size reduction, have failed in clinical studies. Thus, cardioprotection is an unmet clinical need. In the present study, we took a network-assisted systems biology approach to explore the mitochondrial proteomic signature of the myocardium after ischemia, ischemia with direct revascularization, and ischemia with re-establishment of blood flow by postconditioning in a swine model of AMI. Furthermore, network extension with the ENCODE project human regulatory data allowed the prediction of potential transcription factors at play in the response to post-conditioning of the myocardium. Collectively, our results identify cardiac metabolism as a driver of cardioprotection, highlighting a dual role for post-conditioning promoting metabolic reprogramming of the myocardium, and a protective response mediated by VDAC2 and DJ-1 in the mitochondria

DJ-1 administration exerts cardioprotection in a mouse model of acute myocardial infarction.

Cardiovascular diseases, and particularly acute myocardial infarction (MI), are the most common causes of death worldwide. Infarct size is the major predictor of clinical outcomes in MI. The Parkinson's disease associated protein, DJ-1 (also known as PARK7), is a multifunctional protein with chaperone, redox sensing and mitochondrial homeostasis activities. Previously, we provided the evidence for a central role of endogenous DJ-1 in the cardioprotection of post-conditioning. In the present study, we tested the hypothesis that systemic administration of recombinant DJ-1 exerts cardioprotective effects in a mouse model of MI and also explored the associated transcriptional response. We report a significant treatment-induced reduction in infarct size, leukocyte infiltration, apoptosis and oxidative stress. Effects potentially mediated by G-protein-coupled receptor signaling and modulation of the immune response. Collectively, our results indicate a protective role for the exogenously administrated DJ-1 upon MI, and provide the first line of evidence for an extracellular activity of DJ-1 regulating cardiac injury in vivo.This work was supported by grants from: the Spanish Ministry of Science and Innovation and Agencia Estatal de Investigación SAF-2016-76819-R (to LB), MCIN/AEI/ 10.13039/501100011033, Plan Nacional Proyectos Investigación Desarrollo (PID 2019-107160RB-I00 to LB), and PGC 2018-094025-B-I00 (to GV); the Instituto de Salud Carlos III: CIBER-CV and ERA-CVD JTC 2020-023/AC 209-00054 (to LB) and FIS PI19/01687 (to TP). AG is a pre-doctoral fellow from BES-2017-081378. This article is part of AG PhD project at Universitat Autònoma de Barcelona (UAB).S

High-density lipoprotein remodelled in hypercholesterolaemic blood induce epigenetically driven down-regulation of endothelial HIF-1α expression in a preclinical animal model

Altres ajuts: This work was supported by the Plan Nacional de Salud (PNS) from the Spanish Ministry of Science and Innovation and funds FEDER 'Una Manera de Hacer Europa'; a grant from the Spanish Society of Cardiology (Beca FEC Investigacio'n Ba'sica/2016 to G.V); the Instituto de Salud Carlos III (ISCIII); and CIBERCV (to L.B). We thank the support of the Generalitat of Catalunya (Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat,) and the Fundación Investigación Cardiovascular-Fundación Jesus Serra for their continuous support.High-density lipoproteins (HDLs) are circulating micelles that transport proteins, lipids, and miRNAs. HDL-transported miRNAs (HDL-miRNAs) have lately received attention but their effects on vascular cells are not fully understood. Additionally, whether cardiovascular risk factors affect HDL-miRNAs levels and miRNA transfer to recipient cells remains equally poorly known. Here, we have investigated the changes induced by hypercholesterolaemia on HDL-miRNA levels and its effect on recipient endothelial cells (ECs). Pigs were kept on a high-fat diet (HC; n = 10) or a normocholesterolaemic chow (NC; n = 10) for 10 days reaching cholesterol levels of 321.0 (229.7-378.5) mg/dL and 74.0 (62.5-80.2) mg/dL, respectively. HDL particles were isolated, purified, and quantified. HDL-miRNA profiling (n = 149 miRNAs) of HC- and NC-HDLs was performed by multipanel qPCR. Cell cultures of porcine aortic ECs were used to determine whether HDL-miRNAs were delivered to ECs. Potential target genes modulated by miRNAs were identified by bioinformatics and candidate miRNAs were validated by molecular analysis. In vivo effects in the coronary arteries of normocholesterolaemic swine administered HC- or NC-HDLs were analysed. Among the HDL-miRNAs, four were found in different amounts in HC- and NC-HDL (P < 0.05). miR-126-5p and -3p and miR-30b-5p (2.7×, 1.7×, and 1.3×, respectively) were found in higher levels and miR-103a-3p and miR-let-7g-5p (−1.6×, −1.4×, respectively) in lower levels in HC-HDL. miR-126-5p and -3p were transferred from HC-HDL to EC (2.5×; P < 0.05), but not from NC-HDL, by a SRB1-mediated mechanism. Bioinformatics revealed that HIF1α was the miR-126 target gene with the highest predictive value, which was accordingly found to be markedly reduced in HC-HDL-treated ECs and in miR126 mimic transfected ECs. In vivo validation confirmed that HIF1α was diminished in the coronary endothelial layer of NC pigs administered HC-HDL vs. those administered NC-HDL (P < 0.05). Hypercholesterolaemia induces changes in the miRNA content of HDL enhancing miR126 and its delivery to ECs with the consequent down-regulation of its target gene HIF1α

Microvesicles carrying LRP5 induce macrophage polarization to an anti-inflammatory phenotype

Altres ajuts: Fundación Investigación Cardiovascular-Fundación Jesus SerraAltres ajuts: Sociedad Española de Cardiología FEC2019Microvesicles (MV) contribute to cell-to-cell communication through their transported proteins and nucleic acids. MV, released into the extracellular space, exert paracrine regulation by modulating cellular responses after interaction with near and far target cells. MV are released at high concentrations by activated inflammatory cells. Different subtypes of human macrophages have been characterized based on surface epitopes being CD16 macrophages associated with anti-inflammatory phenotypes. We have previously shown that low-density lipoprotein receptor-related protein 5 (LRP5), a member of the LDLR family that participates in lipid homeostasis, is expressed in macrophage CD16 with repair and survival functions. The goal of our study was to characterize the cargo and tentative function of macrophage-derived MV, whether LRP5 is delivered into MV and whether these MV are able to induce inflammatory cell differentiation to a specific CD16 or CD16 phenotype. We show, for the first time, that lipid-loaded macrophages release MV containing LRP5. LDL loading induces increased expression of macrophage pro-inflammatory markers and increased release of MV containing pro-inflammatory markers. Conditioning of fresh macrophages with MV released by Lrp5-silenced macrophages induced the transcription of inflammatory genes and reduced the transcription of anti-inflammatory genes. Thus, MV containing LRP5 induce anti-inflammatory phenotypes in macrophages

Prevention of stroke in patients with chronic coronary syndromes or peripheral arterial disease

Stroke is a common and devastating condition caused by atherothrombosis, thromboembolism, or haemorrhage. Patients with chronic coronary syndromes (CCS) or peripheral artery disease (PAD) are at increased risk of stroke because of shared pathophysiological mechanisms and risk-factor profiles. A range of pharmacological and non-pharmacological strategies can help to reduce stroke risk in these groups. Antithrombotic therapy reduces the risk of major adverse cardiovascular events, including ischaemic stroke, but increases the incidence of haemorrhagic stroke. Nevertheless, the net clinical benefits mean antithrombotic therapy is recommended in those with CCS or symptomatic PAD. Whilst single antiplatelet therapy is recommended as chronic treatment, dual antiplatelet therapy should be considered for those with CCS with prior myocardial infarction at high ischaemic but low bleeding risk. Similarly, dual antithrombotic therapy with aspirin and very-low-dose rivaroxaban is an alternative in CCS, as well as in symptomatic PAD. Full-dose anticoagulation should always be considered in those with CCS/PAD and atrial fibrillation. Unless ischaemic risk is particularly high, antiplatelet therapy should not generally be added to full-dose anticoagulation. Optimization of blood pressure, low-density lipoprotein levels, glycaemic control, and lifestyle characteristics may also reduce stroke risk. Overall, a multifaceted approach is essential to best prevent stroke in patients with CCS/PAD