| First Author | Itani HA | Year | 2016 |
| Journal | Hypertension | Volume | 67 |
| Issue | 6 | Pages | 1218-27 |
| PubMed ID | 27067720 | Mgi Jnum | J:280425 |
| Mgi Id | MGI:6369874 | Doi | 10.1161/HYPERTENSIONAHA.115.07085 |
| Citation | Itani HA, et al. (2016) Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension. Hypertension 67(6):1218-27 |
| abstractText | 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-alpha (TNFalpha) 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-alpha 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. |
