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Published on: July 13, 2018
Angiotensin II induces mitochondrial oxidative stress and mtDNA damage in osteoblasts by inhibiting
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.
Insights
Angiotensin II causes bone dysfunction by increasing mitochondrial oxidative stress and DNA damage in osteoblasts. Targeting the SIRT1-FoxO3a-MnSOD pathway may protect against this bone loss.
Area of Science:
- Biochemistry
- Cell Biology
- Bone Metabolism
Background:
- Angiotensin II is linked to osteoporosis, with some antihypertensive drugs showing protective effects.
- The precise mechanisms of angiotensin II-induced bone dysfunction remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying angiotensin II-induced osteoblast dysfunction.
- To investigate the role of mitochondrial oxidative stress and specific signaling pathways.
Main Methods:
- Osteoblast cell culture treated with angiotensin II.
- Analysis of mitochondrial oxidative stress and DNA damage markers.
- Western blotting and RT-PCR for protein and RNA expression (SIRT1, FoxO3a, catalase, MnSOD).
- Treatment with SIRT1 activator (SRT3025) and MnSOD mimetic (MnTBAP).
Main Results:
- Angiotensin II significantly increased mitochondrial oxidative stress and mitochondrial DNA (mtDNA) damage in osteoblasts.
- Decreased expression of mitochondrial catalase and manganese superoxide dismutase (MnSOD).
- Inhibition of SIRT1 led to FoxO3a hyperacetylation, reducing catalase and MnSOD expression.
- SRT3025 and MnTBAP treatments ameliorated oxidative stress and mtDNA damage.
Conclusions:
- A novel SIRT1–FoxO3a–MnSOD signaling axis mediates angiotensin II-induced mitochondrial damage in osteoblasts.
- This pathway represents a potential therapeutic target for preventing angiotensin II-related bone disorders.
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