Hana Itani
Last active: 4/26/2016

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 (21)

Analysis of Variance Angiotensin II Animals Biomarkers Cells, Cultured Chromatography, High Pressure Liquid Cyclophilin D 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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