Oxidative Impairment of Mitochondrial Electron Transport Chain Complexes in Rostral Ventrolateral Medulla Contributes to Neurogenic Hypertension

Abstract

The role for mitochondrial electron transport chain (ETC) in neurogenic hypertension is unidentified. We evaluated the hypothesis that feedforward depression of mitochondrial ETC functions by superoxide anion (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ) in rostral ventrolateral medulla (RVLM), a brain stem site that maintains sympathetic vasomotor tone and contributes to oxidative stress and neural mechanism of hypertension. Compared with normotensive Wistar-Kyoto rats, spontaneously hypertensive rats exhibited mitochondrial ETC dysfunctions in RVLM in the forms of depressed complex I or III activity and reduced electron coupling capacity between complexes I and III or II and III. Microinjection of coenzyme Q 10 into RVLM of spontaneously hypertensive rats reversed the depressed ETC activity and augmented O 2 ·− production and hypertensive phenotypes. This mobile electron carrier also antagonized the elevated H 2 O 2 in RVLM and vasopressor responses to complex I (rotenone) or III (antimycin A) inhibitor in Wistar-Kyoto or prehypertensive rats. Intracerebroventricular infusion of angiotensin II promoted mitochondrial ETC dysfunctions in Wistar-Kyoto rats, and coenzyme Q 10 or gene knockdown of the p22 phox subunit of NADPH oxidase antagonized the resultant elevation of H 2 O 2 in RVLM. Overexpression of superoxide dismutase or catalase in RVLM of spontaneously hypertensive rats by gene transfer reversed mitochondrial dysfunctions and blunted the augmented O 2 ·− and H 2 O 2 in RVLM. We conclude that O 2 ·− - and H 2 O 2 -dependent feedforward impairment of mitochondrial ETC complexes because of predisposed downregulation of superoxide dismutase or catalase and a cross-talk between NADPH oxidase-derived O 2 ·− and ETC enzymes contribute to chronic oxidative stress in the RVLM of spontaneously hypertensive rats, leading to augmented sympathetic vasomotor tone and hypertension.