Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension.

Itani HA, Dikalova AE, McMaster WG, Nazarewicz RR, Bikineyeva AT, Harrison DG, Dikalov SI
Hypertension. 2016 67 (6): 1218-27

PMID: 27067720 · PMCID: PMC4865418 · DOI:10.1161/HYPERTENSIONAHA.115.07085

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 H2O2 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.

© 2016 American Heart Association, Inc.

MeSH Terms (20)

Analysis of Variance Angiotensin II Animals Biomarkers Cells, Cultured Chromatography, High Pressure Liquid Cyclophilins Disease Models, Animal Endothelium, Vascular Hypertension Lactones Male Mice Mice, Inbred C57BL Mitochondria Oxidative Stress Random Allocation Spiro Compounds Superoxides Vasodilation

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