Altered mitochondrial quality control in autophagy-deficient vascular smooth muscle cells is linked to high-risk atherosclerotic plaque phenotype

Abstract

Atherosclerosis is one of the most common causes of stroke worldwide. Intracranial or extracranial atherosclerosis may occur concomitantly with systemic atherosclerosis involving other arterial beds, such as coronary, or peripheral arteries. A major mechanism of stroke, involves unstable plaque as described in the coronary model. Vascular smooth muscle cells (VSMCs) regulate various aspects of vessel homeostasis, including contraction, dilation, and vessel remodeling. Consequently, VSMCs are one of the main cellular determinants in arterial pathology and several evidence indicates that apoptosis of VSMCs is associated with features of high-risk/vulnerable atherosclerotic lesions. Mitochondrial turnover is an essential aspect of the mitochondrial quality control in which dysfunctional mitochondria are selectively eliminated through autophagy. Even though successful autophagy promotes VSMC survival, it is unclear whether reduced autophagic flux affects mitochondrial quality control of VSMCs in atherosclerotic plaques. By using a mouse model of atherosclerosis carrying a VSMC-specific deletion of the essential autophagy gene Atg7, we observed that impaired VSMC autophagy promotes an unstable plaque phenotype as well as the accumulation of fragmented mitochondria with reduced bioenergetic efficiency and more oxidative stress. Furthermore, we demonstrate that disrupted autophagic flux is linked to defective mitophagy and biogenesis of mitochondria, which exacerbate the apoptosis of VSMCs and plaque vulnerability. Overall, our results indicate that mitochondrial quality control could be a promising therapeutic target to stabilize atherosclerotic plaques and to decrease the risk of stroke.