title: Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension.
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 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.
authors.affiliation: From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Hana A
authors.initials: HA
authors.lastname: Itani
authors.affiliation: From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Dikalova
authors.affiliation: From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: William G
authors.initials: WG
authors.lastname: McMaster
authors.affiliation: From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Nazarewicz
authors.affiliation: From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Alfiya T
authors.initials: AT
authors.lastname: Bikineyeva
authors.affiliation: From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.affiliation: From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN. sergey.dikalov@vanderbilt.edu.
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Dikalov
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011897:Random Allocation; D013141:Spiro Compounds / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
chemical_list: D015415:Biomarkers; D000081406:Peptidyl-Prolyl Isomerase F; D007783:Lactones; C000631446:PPIF protein, mouse; D013141:Spiro Compounds; C121329:sanglifehrin A; D013481:Superoxides; D000804:Angiotensin II; D021983:Cyclophilins
keywords: angiotensin II; cyclophilin D; endothelial oxidative stress; hypertension; inflammatory cytokines; mitochondria; vasorelaxation