PMID: 12714855

Issn Print: 0263-6352

Publication Date: 2003/05/01


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Intracellular signalling pathways regulating vascular NAD(P)H oxidase and hypertension: an opportunity for development of novel antihypertensive agents?

Alex Bobik

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Strong evidence is accumulating to indicate that vascular cells can produce large amounts of reactive oxygen species, including superoxide anion (O–2) and hydrogen peroxide (H2O2) acting as important signalling molecules, and affecting blood pressure, vascular reactivity and cardiovascular structure. They appear to play critical roles in the pathogenesis of a number of cardiovascular diseases, including hypertension [1]. NAD(P)H oxidase appears largely responsible for these reactive oxygen species and can be upregulated by angiotensin II [2]. In humans AT1 receptor therapy not only reduces blood pressure, but also attenuates superoxide anion production, presumably by inhibiting this oxidase [3]. In spontaneously hypertensive rats (SHR) AT1 receptor antagonism lowers vascular superoxide levels by in part down regulating of p22phox expression, a component of the NAD(P)H oxidase system [4]. NAD(P)H oxidase is expressed by endothelial cells, smooth muscle cells and adventitial fibroblasts, and consists of p22phox, gp91phox or one of its Nox homologues, p47phox, p67phox and the membrane bound GTPase, rac1 [1,5,6]. Its importance in blood pressure elevation has been demonstrated using p47phox –/– mice, in whom the rise in blood pressure response to angiotensin II is severely blunted compared to wild-type p47phox +/+ mice [7]. Gene transfer experiments in SHR indicate that superoxide anion is the reactive oxygen species contributing to hypertension [8]. However, although there is a significant body of evidence implicating overactivity/overexpression of NAD(P)H oxidase in hypertension, the mechanisms that regulate its activity and expression in the vasculature are less well understood.
In cultured vascular smooth muscle angiotensin II, platelet-derived growth factor (PDGF-BB) and thrombin potently activate NAD(P)H oxidase whereas, in cultured endothelial cells, angiotensin II, glucocorticoids, vascular endothelial cell growth factor, tumour necrosis factor-alpha and lysophosphatidylcholine all activate NAD(P)H oxidase. In cultured vascular smooth muscle, angiotensin II-induced upregulation of NAD(P)H oxidase activity occurs following serine phosphorylation of p47phox, and may also involve translocation of the phox subunits and de novo protein synthesis [5]. In this issue of the journal, Laplante et al. [9] studied signalling mechanisms that contribute to the enhanced superoxide production by vessels during angiotensin-induced hypertension. Angiotensin II was infused for 12 days into male rats simultaneously treated with either an AT1 receptor antagonist, an inhibitor of tyrosine kinases, a specific MEK inhibitor or α-lipoic acid, an agent which possesses potent antioxidant properties. They demonstrate that angiotensin II is a potent stimulator of NAD(P)H oxidase in smooth muscle cells of hypertensive animals, accounting for almost 70% of the superoxide produced by the aorta; the remainder is apparently produced by the endothelium. Their finding of elevations in vascular superoxide levels in animals made hypertensive by infusing angiotensin II supports previous studies reporting elevations in vascular NAD(P)H oxidase in hypertension [10,11], and further implicate an activated vascular NAD(P)H oxidase in the pathogenesis of hypertension. They also report that (p42/p44)ERK-MAPK phosphorylation is elevated in vessels of hypertensive animals. Treatment with PD98059 not only prevents ERK-MAPK phosphorylation, but also abolishes most of the rise in vascular superoxide levels, directly implicating ERK-MAPK in the signalling cascade leading to angiotensin-mediated increases in NAD(P)H oxidase activity. In addition, because NAD(P)H oxidase derived superoxide anion can also activate ERK-MAPK [12], the generated superoxide anions may further activate MAPK-ERK, thereby amplifying angiotensin II-induced elevations in NAD(P)H oxidase in vessels of hypertensive animals. The reduction in ERK-MAPK phosphorylation by lipoic acid may result from the lower levels of superoxide anion available to activate ERK-MAPK. A number of mechanisms could account for ERK-MAPK-mediated elevation in vascular superoxide levels, including phosphorylation of p47phox. In human neutrophils, formyl-methionyl-leucyl-phenylalanine induces p47phox phosphorylation and NAD(P)H oxidase activation via an ERK-MAPK-dependent pathway [13].

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