Atherosclerosis and endothelial autophagy – ATHENA

Aging and metabolic syndrome are associated with atherosclerosis, a worldwide leading cause of death. Fighting atherosclerosis and its clinical complications is thus a major challenge in public health. However, current treatments target either cardiovascular risk factors or complications of atherosclerosis, but not the disease itself. Unfortunately, we are still lacking preventive measures and treatment against the development of atherosclerosis. Therefore, we need to better understand the mechanisms involved in the initiation and the development of the disease.

Hemodynamic forces regulate atherosclerotic plaque localization. In particular, shear stress resulting from the flowing blood is the major regulator of endothelial activation, an early step in atherosclerotic plaque development: areas exposed to low shear stress --such as the aortic arch-- are prone to develop atherosclerotic lesions, whereas areas exposed to high shear stress are protected. Vascular endothelial cells are capable to integrate changes in hemodynamic forces in order to regulate endothelial atheroprotective functions. Yet, the molecular mechanisms involved in these responses have not been fully explored.

Autophagy is a catabolic process responsible for the degradation of cell components and involved in major cellular functions, including differentiation, degradation of aberrant structures, lifespan extension and cell death. This project will test the hypothesis that low shear athero-prone areas are characterized by inefficient endothelial autophagy, setting the stage for the development of atherosclerotic lesions in a context of metabolic syndrome and aging and that activation of endothelial autophagy flux prevents plaque development.

We already gathered robust preliminary results in murine and human arteries demonstrating that endothelial autophagy is impaired in atheroprone low shear stress areas of the vasculature, due to blockade of autophagy flux resulting from the lack of fusion of autophagosomes with lysosomes. We also have developed new models of endothelial autophagy deficiency in human cells and in mice. Our first data indicate that inefficient endothelial autophagy increases in vitro endothelial apoptosis, senescence and inflammation and augments plaque formation in ApoE-/- mice. These preliminary results strongly corroborate our hypothesis of a causal link between shear stress activation of endothelial autophagy and protection from atherosclerosis. The present project will determine how endothelial autophagy is precisely regulated and the molecular mechanisms linking autophagy to endothelial senescence, inflammation and apoptosis, in particular the role of reactive oxygen species. We will also identify the mechanisms capable to restore appropriate endothelial autophagic flux in cells exposed to low shear stress. Then, we will examine in vivo whether or not activating endothelial autophagy flux in vivo prevents the development of atherosclerotic plaques in mice, in particular in low shear stress atheroprone areas.

The 2 partners have already published together (Kheloufi, Boulanger, Codogno, Rautou. Autosis occurs in the liver of patients with severe anorexia nervosa. Hepatology 2015;62:657-8). Furthermore, they have extensive and complementary expertise in endothelial biology and autophagy and have generated new pilot data demonstrating that endothelial shear stress affects autophagy level and original murine models with endothelial-specific deletion of autophagy, attesting the complete feasibility of the proposed project