Lack of glutathione peroxidase 1 accelerates cardiac-specific hypertrophy and dysfunction in angiotensin II hypertension.

Glutathione peroxidase 1 (Gpx1) plays an important role in cellular defense by converting hydrogen peroxide and organic hydroperoxides to nonreactive products, and Gpx1(-/-) mice, which are characterized by reduced tissue glutathione peroxidase activity, are known to exhibit enhanced oxidative stress. Peroxides participate in tissue injury, as well as the hypertrophy of cultured cells, yet the role of Gpx1 to prevent end organ damage in cardiovascular tissue is not clear. We postulated that Gpx1 deletion would potentiate both aortic and cardiac hypertrophy, as well as mean arterial blood pressure, in response to angiotensin II (AngII). Our results show that short-term AngII markedly increased left ventricular mass, myocyte cross-sectional area, and interventricular septum thickness and decreased shortening fraction in Gpx1(-/-) mice as compared with wild-type animals. On the other hand, AngII resulted in a similar increase in mean arterial blood pressure in wild-type and Gpx1(-/-) mice. Collagen deposition increased in response to AngII, but no differences were found between strains. Vascular hypertrophy increased to the same extent in Gpx1(-/-) and wild-type mice. Collectively, our results indicate that Gpx1 deficiency accelerates cardiac hypertrophy and dysfunction but has no effect on vascular hypertrophy and mean arterial blood pressure and suggest a major role for Gpx1 in cardiac dysfunction in AngII-dependent hypertension.

Nox4 oxidase overexpression specifically decreases endogenous Nox4 mRNA and inhibits angiotensin II-induced adventitial myofibroblast migration.

The vascular adventitia is emerging as an important modulator of vessel remodeling. Adventitial myofibroblasts migrate to the neointima after balloon angioplasty, contributing to restenosis. We postulated that angiotensin II (Ang II) enhances adventitial myofibroblast migration in vitro via reduced nicotinamide-adenine dinucleotide phosphate oxidase-derived H(2)O(2) and that Nox4-based oxidase promotes migration. Ang II increased myofibroblast migration in a concentration-dependent manner, with a peak increase of 1023+/-83%. Rat adventitial myofibroblasts were cotransfected with human Nox4 and human p22-phox plasmids or an empty vector. PCR showed an 8-fold increase in human Nox4 and human p22-phox plasmid expression. Using RT-PCR with primers specifically designed for rat reduced nicotinamide-adenine dinucleotide phosphate oxidases, endogenous Nox levels were determined. Ang II decreased endogenous Nox4 and Nox1 mRNA to 41% and 27% of control, respectively, but had no effect on Nox2. Cotransfection with human Nox4 and human p22-phox plasmids combined with Ang II reduced endogenous Nox4 mRNA levels (37+/-5% of control; P<0.05), whereas it had no significant effect on Nox1 or Nox2. In empty vector-transfected cells, Ang II increased myofibroblast migration by 192+/-32% versus vehicle (P<0.01) while increasing H(2)O(2) (473+/-22% versus control; P<0.001). Cotransfection with human Nox4 and human p22-phox plasmids decreased Ang II-induced migration (46+/-6%; P<0.001) in parallel with attenuation of H(2)O(2) production (23+/-8% versus empty vector; P<0.05). Our data suggest that Nox4 promotes Ang II-induced myofibroblast migration via an H(2)O(2)-dependent pathway. The data also suggest that Nox4 causes feedback inhibition of its own expression in adventitial myofibroblasts.

Targeting reactive oxygen species in hypertension.

PURPOSE OF REVIEW: Hypertension is a major risk factor for vascular diseases such as stroke, myocardial infarction, and renal microvascular disease. The mechanism by which vascular disease develops is complex, and growing evidence suggests that an increase in reactive oxygen species during hypertension is a major contributing factor. NADPH oxidase, the primary source of reactive oxygen species in the cardiovascular system, is a strong candidate for the development of therapeutic agents to ameliorate hypertension and end-organ damage. RECENT FINDINGS: Various scavengers and inhibitors of reactive oxygen species have been proposed for use in animal as well as human studies. While many of these agents are effective at lowering tissue reactive oxygen species levels, their specificity is a serious concern. Our laboratory has developed cell-permeant peptidic inhibitors targeting key interactions among the different NAD(P)H oxidase homologues. One of these inhibitors targeting nox2 and p47-phox interaction has proven useful in attenuating target neoplasia and hypertrophy. SUMMARY: Strategies aimed at specifically inhibiting NAD(P)H oxidase have proven effective in attenuating cardiovascular oxidative stress. The development of new inhibitors targeting novel oxidase homologues appears to hold significant promise for clarifying the physiologic role of these homologues as well as for the development of new antioxidant therapies.