Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension

Abstract

Vascular superoxide (O2•) and inflammation contribute to hypertension. The mitochondria are an important source of O2•; however, the regulation of mitochondrial O2• and the antihypertensive potential of targeting the mitochondria remain poorly defined. Angiotensin II and inflammatory cytokines such as IL17A and TNFα significantly contribute to hypertension. We hypothesized that angiotensin II and cytokines co-operatively induce cyclophilin D (CypD)-dependent mitochondrial O2• production in hypertension. We tested if CypD inhibition attenuates endothelial oxidative stress and reduces hypertension. CypD depletion in CypD−/− mice prevents overproduction of mitochondrial O2• 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 O2• 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 O2• and attenuated hypertension. The functional role of cytokine-angiotensin II interplay was confirmed by co-operative stimulation of mitochondrial O2• by 3-fold in cultured endothelial cells and impairment of aortic relaxation incubated with combination of angiotensin II, IL17A and TNFα 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 O2•, improves vascular relaxation and reduces hypertension.

Oxidative Stress and Hypertensive Diseases

“…Recently it was found that pharmacological inhibition or deletion of CypD in mice prevents ang II induced hypertension. 39 Mitochondrial DNA fragments, indicative of mitochondrial damage, are increased in the urine of hypertensive humans and directly correlate with markers of renal injury in these individuals. 40 …”

Circulating miR-92a expression level in patients with essential hypertension: a potential marker of atherosclerosis

“…[1][2][3][4][5] Although many mechanisms have been elucidated in the pathogenesis of hypertension, such as endothelial dysfunction, 6 sympathetic nervous system overdrive, 7 inflammatory reactions, 8 oxidative stress, 9 gene modifications and impaired angiogenesis, 10 at the molecular level, many aspects of hypertension development are still unknown. 11 MicroRNAs (miRs) are small non-coding RNAs that are key posttranscriptional regulators of gene expression in all eukaryotic cells 12 and have been found to modulate the function of endothelial cells (ECs), 13 smooth muscle cells 14 and macrophages 15 by controlling the expression of chemokines, thereby affecting different stages of atherosclerosis progression.…”

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…, improves vascular relaxation, and reduces hypertension. 50 Cytochrome P450 1B1 is another source of ROS, which may be important in vascular pathobiology of hypertension and atherosclerosis. It contributes to VSMC growth and hypertension, as well as to vascular aging characteristic of elastin breaks and vascular infiltration of macrophages and T lymphocytes.…”