PMID- 30686087 OWN - NLM STAT- MEDLINE DCOM- 20191114 LR - 20191114 IS - 1524-4563 (Electronic) IS - 0194-911X (Linking) VI - 73 IP - 3 DP - 2019 Mar TI - Caloric Restriction Exacerbates Angiotensin II-Induced Abdominal Aortic Aneurysm in the Absence of p53. PG - 547-560 LID - 10.1161/HYPERTENSIONAHA.118.12086 [doi] AB - 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 AAA-related 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 II-induced AAA formation by maintaining an appropriate mitochondrial function. FAU - Gao, Peng AU - Gao P AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). FAU - Zhang, Hexuan AU - Zhang H AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). FAU - Zhang, Qin AU - Zhang Q AD - Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, China (Q.Z., X.F., M.W., G.Y.). FAU - Fang, Xia AU - Fang X AD - Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, China (Q.Z., X.F., M.W., G.Y.). FAU - Wu, Hao AU - Wu H AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). FAU - Wang, Miao AU - Wang M AD - Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, China (Q.Z., X.F., M.W., G.Y.). FAU - Lu, Zongshi AU - Lu Z AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). FAU - Wei, Xiao AU - Wei X AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). FAU - Yang, Gangyi AU - Yang G AD - Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University and Chongqing Clinical Research Center for Geriatrics, China (Q.Z., X.F., M.W., G.Y.). FAU - Yan, Zhencheng AU - Yan Z AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). FAU - Liu, Daoyan AU - Liu D AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). FAU - Zhu, Zhiming AU - Zhu Z AD - From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, China (P.G., H.Z., H.W., Z.L., X.W., Z.Y., D.L., Z.Z.). LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Hypertension JT - Hypertension (Dallas, Tex. : 1979) JID - 7906255 RN - 0 (Trp53 protein, mouse) RN - 0 (Tumor Suppressor Protein p53) RN - 11128-99-7 (Angiotensin II) SB - IM MH - Angiotensin II/toxicity MH - Animals MH - Aorta, Abdominal/metabolism/pathology MH - Aortic Aneurysm, Abdominal/chemically induced/genetics/*therapy MH - Caloric Restriction/*methods MH - Disease Models, Animal MH - Energy Metabolism/*physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Muscle, Smooth, Vascular/*metabolism MH - Signal Transduction MH - Tumor Suppressor Protein p53/*genetics/metabolism OTO - NOTNLM OT - angiotensin II OT - aortic aneurysm, abdominal OT - caloric restriction OT - mice OT - tumor suppressor protein p53 EDAT- 2019/01/29 06:00 MHDA- 2019/11/15 06:00 CRDT- 2019/01/29 06:00 PHST- 2019/01/29 06:00 [pubmed] PHST- 2019/11/15 06:00 [medline] PHST- 2019/01/29 06:00 [entrez] AID - 10.1161/HYPERTENSIONAHA.118.12086 [doi] PST - ppublish SO - Hypertension. 2019 Mar;73(3):547-560. doi: 10.1161/HYPERTENSIONAHA.118.12086.