CARDINAL - Cardiomyocyte-derived vesicular non coding RNAs and post-ischemic cardiac remodeling

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Cardiovascular diseases (CVD) are the main cause of mortality in nearly all European countries despite the best state-of-the-art treatments. Diabetes, a global health concern with an estimated 347 million affected people worldwide and a projected 50% increase in incidence during the next decade, increases by about 3-fold the risk of CVD. A striking failure in the treatment of diabetes is the inability of lifestyle- or drug-based interventions to impact on the excess risk of diabetes-induced adverse ventricular remodelling and cardiac dysfunction. Hence, efforts are directed towards pivotal pathways shaping cardiac homeostasis. After myocardial infarction, the cardiac tissue release several soluble chemokines, cytokines, and growth factors, which induce inflammatory response to shape the repair process. However, there are several open questions about how the myocardium initiates the local repair process or how it manipulates inflammatory reaction. In addition, fibroblast-induced fibrosis is also an integral component of cardiac remodelling and informations are lacking concerning the nonpermissive mechanisms induced by the ischemic milieu. Our hypothesis is that extracellular vesicles (EVs) are released locally in the heart following myocardial infarction and that the transfer of their non-coding RNA content affects the local inflammatory response as well as fibroblast-dependent activity and subsequently repair mechanisms. This proposal aims at 1-characterizing and analyzing the non-coding RNA (microRNAs and long non-coding RNAs) cargo of EVs isolated from infarcted myocardium in a type-2 diabetic murine model, from cultured cardiomyocytes cell line and induced pluripotent cell-derived cardiomyocytes, 2- identifying and exploring the impact of EV transfer to target cells in vitro and in vivo in the context of diabetes, and identifying targets of functionally transported non-coding RNAs to recipient cells, including fibroblasts and inflammatory cells, 3- designing therapeutic approaches by either delivering beneficial noncoding RNA oligonucleotides using synthetic liposomes or inhibiting detrimental specific noncoding RNAs using LNA/GapmeRs. This projects brings together one german and two french partners with leading expertise in inflammation and fibrosis after myocardial infarction and in extracellular vesicle and noncoding RNA analysis. Their preliminary data show specific noncoding RNA packaging into extracellular vesicles of cardiomyocyte origin produced either in vitro or in vivo following myocardial infarction, and vesicle targeting to recipients fibroblasts and inflammatory cells. These findings will help decipher the molecular mechanisms governing the functional consequences of EVs in the infarcted heart in order to design new therapeutic tools for treating cardiac ischemic diseases in the context of diabetes.