Endothelin-1 Increases Vascular Superoxide via Endothelin _A –NADPH Oxidase Pathway in Low-Renin Hypertension

Abstract

Background-Angiotensin II-induced hypertension is associated with NAD(P)H oxidase-dependent superoxide production in the vessel wall. Vascular superoxide level is also increased in deoxycorticosterone acetate (DOCA)-salt hypertension, which is associated with a markedly depressed plasma renin activity because of sodium retention. However, the mechanisms underlying superoxide production in low-renin hypertension are undefined. Methods and Results-This study investigated (1) whether and how endothelin-1 (ET-1), which is increased in DOCA-salt hypertensive rats, contributes to arterial superoxide generation and (2) the effect of gene transfer of manganese superoxide dismutase and endothelial nitric oxide synthase. Both superoxide and ET-1 levels were significantly elevated in carotid arteries of DOCA-salt rats compared with that of the sham-operated controls. ET-1 concentration-dependently stimulated superoxide production in vitro in carotid arteries of normotensive rats. The increase in arterial superoxide in both ET-1-treated normotensive and DOCA-salt rats was reversed by a selective ET A receptor antagonist, ABT-627, the flavoprotein inhibitor diphenyleneiodonium, and the NADPH oxidase inhibitor apocynin but not by the nitric oxide synthase inhibitor N -L-arginine methyl ester or the xanthine oxidase inhibitor allopurinol. Furthermore, in vivo blockade of ET A receptors significantly reduced arterial superoxide levels, with a concomitant decrease of systolic blood pressure in DOCA-salt rats. Ex vivo gene transfer of manganese superoxide dismutase or endothelial nitric oxide synthase also suppressed superoxide levels in carotid arteries of DOCA-salt rats. Conclusions-These findings suggest that ET-1 augments vascular superoxide production at least in part via an ET A /NADPH oxidase pathway in low-renin mineralocorticoid hypertension.

Superoxide anion is elevated in sympathetic neurons in DOCA-salt hypertension via activation of NADPH oxidase

“…sympathetic ganglia; phorbol ester; reduced nicotinamide adenine dinucleotide phosphate oxidase; hypertension; deoxycorticosterone acetate VASCULAR ENDOTHELIAL CELLS, smooth muscle cells, and fibroblasts generate reactive oxygen species (ROS), such as O 2 Ϫ ⅐ and H 2 O 2 . ROS play critical roles in both normal and pathophysiological states of vascular cells, including the modulation of redox-sensitive signaling pathways and gene expression, or in the pathophysiology of hypertension and atherosclerosis (16,22,26,36). Several models of hypertension are associated with an increase in vascular O 2 Ϫ ⅐ (41, 42), and this increased O 2 Ϫ ⅐ may quench the endogenous vasodilator nitric oxide (NO) to cause a loss of NO bioactivity in the vessel wall and impair the endothelium-dependent vasorelaxation, resulting in hypertension (26).…”

“…II-infused rats (24) and in DOCA-salt hypertensive rats (42) can be reversed by antioxidant enzyme, endothelial NO synthase (34), or superoxide dismutase (26). ROS can also induce the expression of cardiovascular-related genes, such as those for adhesion molecules and vasoactive substances.…”

Carotid atherosclerosis in elderly hypertensive patients: potential role of endothelin and plasma antioxidant capacity

“…ET-1 increases oxidative stress through the activation of NAD(P)H oxidase-a key enzymatic source for superoxide anion in the vascular wall. 12,13,16,27 Excessive oxidative stress activates several redox-sensitive signalling pathways resulted in activation of MAP kinase family, tyrosine kinases, transcription factors nuclear factor kB, activator protein-1, vascular cellular adhesion molecule-1 and increase release of proinflammatory cytokines. 8,13,26,28,29 The contribution of ET-1, NAD(P)H oxidase and reactive oxygen species in VSMC proliferation was confirmed by the possibility of blocking this process by pre-incubation of VSMC with ET A receptor antagonist, 13 NAD(P)H oxidase inhibitor 12,16 or with antioxidants; 12,13,16 however, it was documented for extracellular superoxide dismutase, 13 and among the antioxidants included in FRAP for ascorbic acid.…”

“…12,13,16,27 Excessive oxidative stress activates several redox-sensitive signalling pathways resulted in activation of MAP kinase family, tyrosine kinases, transcription factors nuclear factor kB, activator protein-1, vascular cellular adhesion molecule-1 and increase release of proinflammatory cytokines. 8,13,26,28,29 The contribution of ET-1, NAD(P)H oxidase and reactive oxygen species in VSMC proliferation was confirmed by the possibility of blocking this process by pre-incubation of VSMC with ET A receptor antagonist, 13 NAD(P)H oxidase inhibitor 12,16 or with antioxidants; 12,13,16 however, it was documented for extracellular superoxide dismutase, 13 and among the antioxidants included in FRAP for ascorbic acid. 12,16 It was also shown that vitamin C inhibited activation of mitogen-activated protein kinase and VSMC proliferation in cultured rat aortic smooth muscle cells, 26 and in an in vivo experiment it was demonstrated that vitamin C supplementation decreased activation of NADPH oxidase and superoxide anion generation, prevented vascular hypertrophy and increased plasma total antioxidant status and superoxide dismutase in arterial wall in stroke-prone spontaneously hypertensive rats.…”

“…10,11 It has been documented that ET-1 is involved in the interplay between oxidative stress and the development of hypertension-and diabetes-induced cardiovascular complications. 12,13 Reactive oxygen species increase ET-1 production in endothelial and VSMCs, 14,15 and on the other hand, they function as intracellular messengers modulating the ET-1 signalling pathway. 12,16 As we have shown recently in hypertensive and diabetic patients, higher plasma ET-1 level is independently associated with lower plasma antioxidant capacity (assessed by ferricreducing ability of plasma-FRAP) and decreased vitamin C concentration, which may be a result of increased oxidative stress in these diseases.…”