title: Angiotensin II induces mitochondrial oxidative stress and mtDNA damage in osteoblasts by inhibiting SIRT1–FoxO3a–MnSOD pathway.
abstract: Previous report showed that angiotensin II accelerates osteoporosis, and recent clinical studies suggest that several antihypertensive drugs, especially angiotensin-converting enzyme inhibitors, reduced bone fractures. However, the underling mechanism by which angiotensin II induces bone dysfunction is largely unknown. Here in this study, we show that angiotensin II induces mitochondrial oxidative stress and mitochondrial DNA (mtDNA) damage. We find that the protein and RNA levels of mitochondrial catalase and manganese superoxide dismutase (MnSOD) are decreased in osteoblasts in the presence of angiotensin II. Further, we show that angiotensin II inhibits the protein level of SIRT1, but not SIRT3, which results in the hyperacetylation of the forkhead box O3a (FoxO3a) and inhibition of the expression of catalase and MnSOD. Finally, we show that SRT3025 (Sirt1 activator) and Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP, a MnSOD mimetics) can markedly reduce mitochondrial oxidative stress and mtDNA damage. In summary, we identify a novel SIRT1–FoxO3a–MnSOD axis in angiotensin II-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Guangsi
authors.initials: G
authors.lastname: Shen
authors.forename: Chen
authors.initials: C
authors.lastname: Yu
authors.forename: Guangfei
authors.initials: G
authors.lastname: Li
authors.forename: Junkang
authors.initials: J
authors.lastname: Shen
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
authors.forename: Youjia
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D000804:Angiotensin II; D002374:Catalase; D013482:Superoxide Dismutase; D056564:Sirtuin 1