Altered mitochondrial quality control in Atg7-deficient VSMCs promotes enhanced apoptosis and is linked to unstable atherosclerotic plaque phenotype

Hripsimé Nahapetyan,Marie-Hélène Grazide,Elisa Grousset,Elodie Mucher,Manon Moulis,Cécile Vindis,Wim Martinet,Meyer Elbaz,Julien Faccini

doi:10.1038/s41419-019-1400-0

Abstract

Vascular smooth muscle cells (VSMCs) are one of the main cellular determinants in arterial pathology. A large body of evidence indicates that death of VSMCs is associated with features of high-risk/vulnerable atherosclerotic plaques. Mitochondrial turnover is an essential aspect of the mitochondrial quality control in which dysfunctional mitochondria are selectively eliminated through autophagy and replaced through expansion of preexisting mitochondria. 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 apolipoprotein E-deficient (ApoE−/−) mice carrying a VSMC-specific deletion of the essential autophagy gene Atg7, we show in the present study 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 VSMC apoptosis and in turn plaque vulnerability. Overall, our data indicate that mitochondrial quality control is a promising therapeutic target to stabilize atherosclerotic plaques.

Highlights

Vascular smooth muscle cells (VSMCs) regulate various aspects of vessel homeostasis, including contraction, dilation, and vessel remodeling
We investigated whether defective autophagy in VSMCs could impact mitochondrial quality control and whether this affected atherosclerotic plaque phenotype and development
Autophagy deficiency in VSMCs exacerbates the progression of atherosclerotic lesions Atg7F/FTagln-Cre+ mice harboring a deletion of the essential autophagy gene Atg[7] in VSMCs and their wildtype counterparts (Atg7+/+Tagln-Cre+) were crossbred with ApoE−/− mice to generate Atg7F/FTagln-Cre+, ApoE−/− and Atg7+/+Tagln-Cre+, ApoE−/− mice, respectively

Summary

Introduction

Vascular smooth muscle cells (VSMCs) regulate various aspects of vessel homeostasis, including contraction, dilation, and vessel remodeling. The degradation products are transported back to the cytoplasm where they can be reused for biosynthesis or energy production This process is important for maintaining cellular homeostasis and deregulated autophagy has been implicated in the pathogenesis of a wide array of diseases[5]. Mitophagy can occur in specific developmental processes, such as the maturation of erythrocytes[11], and following pathological mitochondrial damage to eliminate altered mitochondria and to prevent cell death[12]. During the early stages of apoptosis, alterations in mitochondrial morphology (fragmentation and remodeling) and function (decline in mitochondrial membrane potential and increase in radical production) are observed All these events are known to be prerequisites for the initiation of mitophagy[13,14]. Selective elimination of dysfunctional mitochondria reduces the release of cytochrome c and other pro-apoptotic factors into the cytosol that activate downstream cell death pathways[15]

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Conclusion