High Density Lipoprotein (HDL) et PI3K signaling in atherosclerosis.
Atherosclerosis is initiated by endothelial dysfunction which leads to lipids accumulation, mainly cholesterol, within the vascular wall, associated to impaired excess cholesterol removal by High Density Lipoprotein (HDL). Later on, cholesterol and lipid deposits induce an inflammatory and fibro-proliferative response, leading to the formation of an atherosclerotic plaque. When the plate breaks, it forms a thrombus responsible for myocardial infarction, stroke or acute lower limb ischemia, depending on its location. The standard treatment is to perform angioplasty with placement of arterial stent, which restores arterial flow but might have adverse effects, such as restenosis and thrombotic complications.
Our work is focused on two research axes, with the common goal to identify therapeutic targets for the prevention and treatment of cardiovascular and metabolic diseases.
Axis 1: HDL & F1-ATPase / P2Y pathways in cardiovascular and metabolic diseases
Despite considerable progresses in prevention and therapy,atherosclerotic cardiovascular diseases remain the most frequent cause of death (> 50% in Europe). Current preventive and therapeutic measures, notably lowering of low-density lipoprotein (LDL) cholesterol and blood pressure can probably save 30%. For the remaining 70% there will only be hope if new targets for therapeutic intervention are identified. In this context, high-density lipoprotein (HDL) cholesterol, for which atheroprotective properties have been supported byepidemiological, clinical and basic research, is one of the more interesting targets for treatments that will further reduce cardiovascular morbidity and mortality.
Most of the atheroprotectiveeffect of HDL is ascribedto its role in reverse cholesterol transport, a process wherebyHDL removes cholesterol from atherosclerotic foam cells and delivers it to the liver for biliary excretion.In addition, HDL exerts various direct anti-inflammatory, anti-thrombotic, anti-oxidant and cytoprotective effects on the vasculature.
However, HDL is not easy to target, mainly because its atheroprotective functions are determined by the quality of HDL particles rather than the quantity of HDL-cholesterol. Therefore, HDL therapies that lower cardiovascular risk are NOT yet available.
Hence,major public health and economic and societal interest exists for
i.The better characterization of cellular and molecular partners involved in HDL functions for the development of new drugs able to affect specific mechanisms rather than increasing HDL-C levels.
ii. To identifyHDL-related biomarkers better than HDL-cholesterol level for assessing cardiovascular risk(diagnostic and prognostic).
In this context, our team has previously demonstrated diverse roles of the cell surface F1-ATPase as a receptor for apoA-I (the main HDL apolipoprotein) coupled to purinergic P2Y receptors and involved in metabolic and vascular functions of HDL. The clinical relevance of this F1-ATPase/P2Ys axis in HDL functions in humans has recently been supported by the identification of serum F1-ATPase inhibitor (IF1) as an independent determinant of HDL-C and coronary artery disease risk.
Hence our research aims to exploreF1-ATPase / P2Ys pathway(s) from the molecular level to an integrated approach to pre-clinical models and to clinical investigation.
Specifically, we want to:
1.Resolve the pathways and regulators which direct ecto-F1-ATPase to its atypical location in the plasma membrane as well as the signaling cascades elicited by the interaction of apoA-I (main HDL protein) with the ecto-F1-ATPase/P2Y partners.
2.Unravel the pathophysiological relevance of the ecto-F1-ATPase/P2Y axis to the HDL atheroprotective functions in reverse cholesterol transport and endothelial protection. This will be performed by using novel tools developed within the consortium such as pre-clinical animal models and new pharmacological molecules targeting ecto-F1-ATPAse/P2Y axis.
3.Explore the potential of new HDL-related biomarkers, including IF1, as a diagnostic and prognostic biomarker for cardiovascular disease.
Thus, this research axis has the potential to co-developnew drugs as a therapy for cardiovascular disease and a companion diagnostic test. It willthus permit a biologically and clinical based reassessment of the optimal therapeutic strategy for targeting HDL, with the ultimate goal of proposing a theranostic approach inthe diagnosis/prognosis, prevention and treatment of cardiovascular diseases.
Axis 2: Phosphoinositide 3-kinase in cardiovascular diseases: From molecular mechanisms to new therapeutic approaches.
Phosphoinositide 3-kinases (PI3K) generate lipid second messengers that control a wide range of biological processes such as survival, growth, metabolism or cell migration. Thus, PI3K pathways deregulations are found in several diseases including cardiovascular diseases (CVD). In multicellular organisms, this family of kinases is divided in 3 classes based on structural and biochemical characteristics: Classes IA and IB, II and III. Recent evidences demonstrate that they exert non-redundant and opposite functions. Whereas class Ia enzymes control transcriptional and survival pathways through AKT signaling and block autophagy through mTOR activation, the class III (Vps34) is an indispensable actor of cell trafficking and autophagy. Thus, more than 25 years after their discovery, their involvement in autophagy and cell regulation makes PI3K attractive targets to modulate cell homeostasis especially in vascular cells.
Our projects propose to decipher signaling pathways involving these kinases in control of endothelial and smooth muscle cell homeostasis in response to arterial stress including mechanical and oxidative stress. Our research is divided in three main axis:
1- Mechanisms involved in EC homeostasis and especially the role of class II PI3K in primary cilium/autophagy
2 - Investigation of class I PI3K disregulation in Smooth Muscle Cells dysfunction in disturbed metabolic conditions
3 - Evaluation of new therapeutic strategies targeting PI3K/mTOR for arterial devices to prevent complication of atherosclerosis treatment in high-risk population of CVD.
Thus, our aim is to translate our fundamental research into clinical perspectives thanks to a close collaboration with the interventional cardiology department of CHU.
Combining fundamental, physiopathology and clinical approaches, this research axis aims to better understand the cellular responses involved in atherosclerosis and its complications in order to discover new therapeutic approaches in cardiovascular diseases.
These team projects are funded by the European Regional Development Fund (FEDER - THERANOVASC), Occitanie region (THERANOVASC & HEPATOCARE), Fondation de France (FDF), Foundation for Medical Research (FRM) and French National Research Agency (ANR).