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• W2340940178 abstract "Vascular superoxide (O˙ 2 - ) and inflammation contribute to hypertension. The mitochondria are an important source of O˙ 2 - ; however, the regulation of mitochondrial O˙ 2 - and the antihypertensive potential of targeting the mitochondria remain poorly defined. Angiotensin II and inflammatory cytokines, such as interleukin 17A and tumor necrosis factor-α (TNFα) significantly contribute to hypertension. We hypothesized that angiotensin II and cytokines co-operatively induce cyclophilin D (CypD)–dependent mitochondrial O˙ 2 - production in hypertension. We tested whether CypD inhibition attenuates endothelial oxidative stress and reduces hypertension. CypD depletion in CypD −/− mice prevents overproduction of mitochondrial O˙ 2 - in angiotensin II–infused mice, attenuates hypertension by 20 mm Hg, and improves vascular relaxation compared with wild-type C57Bl/6J mice. Treatment of hypertensive mice with the specific CypD inhibitor Sanglifehrin A reduces blood pressure by 28 mm Hg, inhibits production of mitochondrial O˙ 2 - by 40%, and improves vascular relaxation. Angiotensin II–induced hypertension was associated with CypD redox activation by S-glutathionylation, and expression of the mitochondria-targeted H 2 O 2 scavenger, catalase, abolished CypD S-glutathionylation, prevented stimulation mitochondrial O˙ 2 - , and attenuated hypertension. The functional role of cytokine–angiotensin II interplay was confirmed by co-operative stimulation of mitochondrial O˙ 2 - by 3-fold in cultured endothelial cells and impairment of aortic relaxation incubated with combination of angiotensin II, interleukin 17A, and tumor necrosis factor-α which was prevented by CypD depletion or expression of mitochondria-targeted SOD2 and catalase. These data support a novel role of CypD in hypertension and demonstrate that targeting CypD decreases mitochondrial O˙ 2 - , improves vascular relaxation, and reduces hypertension." @default.
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• W2340940178 date "2016-06-01" @default.
• W2340940178 modified "2023-10-13" @default.
• W2340940178 title "Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension" @default.
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• W2340940178 doi "https://doi.org/10.1161/hypertensionaha.115.07085" @default.
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