Altered mitochondrial quality control in Atg7-deficient VSMCs promotes enhanced apoptosis and is linked to unstable atherosclerotic plaque phenotype.,Cell Death & Disease

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Altered mitochondrial quality control in Atg7-deficient VSMCs promotes enhanced apoptosis and is linked to unstable atherosclerotic plaque phenotype.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-02-11 , DOI: 10.1038/s41419-019-1400-0
Hripsimé Nahapetyan _{1,

2} , Manon Moulis _{1,

2} , Elisa Grousset _{1,

2} , Julien Faccini ₁ , Marie-Hélène Grazide _{1,

2} , Elodie Mucher _{1,

2} , Meyer Elbaz _{1,

2,

3} , Wim Martinet ₄ , Cécile Vindis _{1,

2}

Affiliation

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.

中文翻译：

Atg7缺陷型VSMC中线粒体质量控制的改变促进细胞凋亡增强，并与不稳定的动脉粥样硬化斑块表型有关。

血管平滑肌细胞（VSMC）是动脉病理学中主要的细胞决定因素之一。大量证据表明，VSMC的死亡与高风险/易患动脉粥样硬化斑块的特征有关。线粒体更新是线粒体质量控制的一个重要方面，其中功能障碍的线粒体通过自噬选择性地消除，并通过扩展先前存在的线粒体而被替代。尽管成功的自噬促进了VSMC的存活，但尚不清楚自噬通量的降低是否会影响动脉粥样硬化斑块中VSMC的线粒体质量控制。通过使用载脂蛋白E缺陷（ApoE-/-）小鼠携带必需自噬基因Atg7的VSMC特异性缺失，我们在本研究中显示受损的VSMC自噬会促进不稳定的噬菌斑表型，以及线粒体碎片的堆积，降低了生物能效率，增加了氧化应激。此外，我们证明破坏的自噬通量与线粒体的缺陷线粒体和生物发生有关，这加剧了VSMC凋亡，进而加剧了斑块易损性。总体而言，我们的数据表明线粒体质量控制是稳定动脉粥样斑块的有希望的治疗目标。

更新日期：2019-02-11

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