Caloric Restriction Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysm in the Absence of p53
Caloric Restriction Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysm in the Absence of p53
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在 p53 缺失的情况下，热量限制会加剧血管紧张素 II 诱导的腹主动脉瘤
DOI：
10.1161/hypertensionaha.118.12086
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发表时间：
2019-03-01
期刊：
影响因子：
8.3
通讯作者：
Zhu, Zhiming
中科院分区：
文献类型：
--
作者：
Gao, Peng;Zhang, Hexuan;Zhu, Zhiming
p53依赖性血管平滑肌细胞衰老是腹主动脉瘤（AAA）的关键病理过程。热量限制 (CR) 是一种防止 AAA 形成的非药物干预措施。然而，p53对于CR的保护作用是否是不可或缺的仍不清楚。在本研究中，我们研究了 p53 在 CR 在 AAA 形成中发挥有益作用的必要性及其潜在机制。我们对 p53(+/+) 和 p53(-/-) 小鼠进行 12 周的 CR，然后检查 Ang II（血管紧张素 II）诱导的 AAA 形成的发生率。我们发现 CR 和 p53 敲除都会减少 Ang II 诱导的 AAA 形成；然而，CR 显着增加了 p53(-/-) 小鼠中 AAA 形成的发生率并加剧了主动脉弹性蛋白降解，并伴有血管衰老增加、活性氧生成和能量产生减少。线粒体呼吸活性分析表明，CR 血清处理后的 p53(-/-) 血管平滑肌细胞中线粒体呼吸异常是由功能失调的复合物 IV 引起的。从机制上讲，p53 的消融通过抑制 SCO2（细胞色素 C 氧化酶组装蛋白 2）依赖性线粒体复合物 IV 活性，几乎完全阻断了 CR 的保护作用。 SCO2的过表达恢复了CR对拮抗Ang II诱导的AAA相关分子表达和p53(-/-)血管平滑肌细胞中活性氧生成的有益作用。总之，我们的研究结果表明，血管平滑肌细胞中 p53 的存在对于 CR 通过维持适当的线粒体功能而在 Ang II 诱导的 AAA 形成中发挥保护作用至关重要。
p53-dependent vascular smooth muscle cell senescence is a key pathological process of abdominal aortic aneurysm (AAA). Caloric restriction (CR) is a nonpharmacological intervention that prevents AAA formation. However, whether p53 is indispensable to the protective role of CR remains unknown. In this study, we investigated the necessity of p53 in the beneficial role of CR in AAA formation and the underlying mechanisms. We subjected p53(+/+) and p53(-/-) mice to 12 weeks of CR and then examined the incidence of Ang II (angiotensin II)-induced AAA formation. We found that both CR and p53 knockout reduced Ang II-induced AAA formation; however, CR markedly increased the incidence of AAA formation and exacerbated aortic elastin degradation in p53(-/-) mice, accompanied by increased vascular senescence, reactive oxygen species generation, and reduced energy production. Analysis of mitochondrial respiratory activity revealed that dysfunctional complex IV accounts for the abnormal mitochondrial respiration in p53(-/-) vascular smooth muscle cells treated by CR serum. Mechanistically, ablation of p53 almost totally blocked the protective role of CR by inhibiting SCO2 (cytochrome C oxidase assembly protein 2)-dependent mitochondrial complex IV activity. Overexpression of SCO2 restored the beneficial effect of CR on antagonizing Ang II-induced expression of AAArelated molecules and reactive oxygen species generation in p53(-/-) vascular smooth muscle cells. Together, our findings demonstrate that the existence of p53 in vascular smooth muscle cells is critical to the protective role of CR in Ang IIinduced AAA formation by maintaining an appropriate mitochondrial function.