Caloric Restriction Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysm in the Absence of p53.
HYPERTENSION(2019)
Abstract
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.
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Key words
angiotensin II,aortic aneurysm, abdominal,caloric restriction,mice,tumor suppressor protein p53
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