CV Science

Stéphanie Barrere-Lemaire PhD Biology and Health

Course and current status

My research activity is focussed on the study of the mechanisms of cell death specifically activated during myocardial infarction and the developement of cardioprotection strategies to fight ischemia-reperfusion injury. During my Ph.D. at the University of Montpellier, my thesis project was to investigate the pathophysiological role of calcium channels in human cardiac cells. This thesis work in cardiac electrophysiolgy allowed identifying a novel calcium conductance through Na⁺ channels, I_CaTTX, in pathological human cardiac myocytes. During my postdoctoral period at the University of San Diego in California, working on the developement of genetically modified mouse models, I contributed to the evidence of novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineage. From 1998 and 2004, my research project as Chargé de recherche at the CNRS at the Institute of Human Genetics in Montpellier was focussed on the study of calcium homeostasis in cardiac cells in pathological conditions. Since 2004, my project has been dedicated to the study of the pathophysiology of acute myocardial infarction (AMI). Indeed, the only way to save the myocardium during the acute phase is to reperfuse the myocardium as soon as possible, either by angioplasty or thrombolysis. However, like for many other treatments, reperfusion is associated with deleterious side effects called reperfusion injury, leading to the death of cardiac cells previously threatened by ischemia. The challenge now is to find the way to specifically abrogate these deleterious side effects in order to develop new pharmacological treatments for AMI patients.

To do this, we now pursue two main objectives : (i) to investigate the cell death mechanisms that are specifically activated at the onset of reperfusion; (ii) to study the endogenous mechanisms of cardioprotection including survival pathways and electrical control of heart rate. Our goal in fine is to identify new targets and to develop cardioprotective strategies. We have developed cutting-edge in vivo, ex vivo and in vitro models of cardiac pathology and take benefits of state of the art technologies and platforms available in our campus, including electrophysiology, cell biology, genomics, surgery, echocardiography and biomarkers analysis.

Scientific summary

Our project is focused on the study of the cellular and molecular mechanisms underlying cardiac cell death during ischemic injury. In 2007, we demonstrated using Death Domain-associated protein 6 dominant negative (DAXX-DN) transgenic mice that the FAS:DAXX-dependent death receptor pathway plays a major role in myocardial IR injury. Since, we developed peptides interfering with the downstream cascade of the FAS receptor including also the FAS-DAXX (Fas-Associated protein with Death Domain) pathway (Cardiovasc res 2019). The impact of this new strategy to save the myocardium is enhanced by the negative results of all clinical trials based on targeting the intrinsic mitochondrial pathway of apoptosis. In parallel, our strategy was to address and mimic the molecular mechanisms underlying ischemic postconditioning considered as a gold standard in cardioprotection. Based on a previous transcriptomic study, we evidenced the presence of metabotropic glutamate 1 receptor (mGluR1) at the surface membrane of ventricular myocytes and showed that their stimulation by glutamate at the onset of reperfusion leads to decreased infarct size (anti-apoptotic effects and activation of PI3kinase-Akt survival pathway) and improved cardiac performance (Cardiovasc Res 2017). This study provides the first demonstration that cardiac mGluR1 activation might represent a putative strategy to prevent IR injury. Our team was successful in this approach to provide cardioprotection in preclinical mouse models (Cardiovasc Res 2017), a first step for the development of new therapeutic strategies targeting IR injury.

In addition, with the support of our LabEx consortium (ICST) we have shown that a combined therapy, based on a Traditional Chinese Medicine providing strong neuroprotective effects in stroke patients and in preclinical models, clearly exhibited potent cardioprotective effects in our murine myocardial IR injury model (Sci Rep 2017). Results of our translational study suggests that cardioprotection strategies should consider combined therapies for the clinical translation.