Coronary Microvascular Endothelial Cell Redox State in Left Ventricular Hypertrophy

Abstract

Left ventricular hypertrophy (LVH) is associated with elevated plasma angiotensin II (Ang II) levels and endothelial dysfunction. The relationship between Ang II and endothelial dysfunction remains unknown, however, but it may involve an alteration in endothelial cell redox state. We therefore investigated the effect of Ang II on NADH/NADPH oxidase-mediated superoxide anion (O(2)(-)) production by cultured guinea pig coronary microvascular endothelial cells (CMVEs) and CMVEs freshly isolated from a guinea pig, pressure-overload model of LVH. Lucigenin chemiluminescence was used to measure O(2)(-) production in the particulate fraction of CMVE lysates. In cultured cells, incubation with Ang II (0.1 nmol/L to 1 micromol/L for 18 hours) resulted in significant (P<0.01) increases in both NADH- and NADPH-dependent O(2)(-) production, with a peak effect at 1 nmol/L. The latter was significantly (P<0.01) inhibited by the AT(1) receptor antagonist losartan (1 micromol/L for 18 hours). In contrast, the O(2)(-) response to Ang II (0.1 nmol/L to 1 micromol/L for 18 hours) was largely unaffected by concomitant exposure to the AT(2) antagonist PD 123319 (1 micromol/L). In freshly isolated CMVEs from nonoperated animals, NADH- and NADPH-dependent O(2)(-) production was not different from that in sham-operated animals but was significantly (P<0.05) elevated in the aortic-banded animals. Plasma Ang II levels were significantly (P<0.001) elevated in the aortic-banded (1.25+/-0.12 microg/L, n=12) compared with sham-operated animals (0.63+/-0.06 microg/L, n=12). These data suggest that the endothelial dysfunction associated with LVH may be due, at least in part, to the Ang II-induced upregulation of NADH/NADPH oxidase-dependent O(2)(-) production.

Angiotensin II Type 1 Receptor Blocker Attenuates Myocardial Remodeling and Preserves Diastolic Function in Diabatic Heart

“…Ang II can activate NAD(P)H oxidase, the most important vascular enzymatic source of superoxide production (33). Therefore, the activation of the renin-angiotensin system may contribute to increased oxidative stress through the expression of an NAD(P)H-dependent oxidase in these settings (34,35). We have recently demonstrated that overexpression of glutathione peroxidase (GSHPx), an antioxidant enzyme, improved LV diastolic function and also reduced myocyte hypertrophy, apoptosis and interstitial fibrosis in DM (6).…”

Effects of Angiotensin II on Nitric Oxide Generation in Proliferating and Quiescent Rat Coronary Microvascular Endothelial Cells

“…However, once the local concentrations of Ang II reach a certain level, the endothelium is induced by Ang II to synthesize/release excess levels of NO and thereby compensates for its contractile effects on VSMC. This bimodal regulation by Ang II is not unique to NO, as O2 formation via NAD(P)H oxidase in guinea pig CMEC (40), adventitial rabbit fibroblasts, and human umbilical vein ECs (HUVEC) (41) has also been reported to induce AT1 receptor in a time-and dose-dependent manner, and to partially inhibit AT2-receptor, also in a time-and dose-dependent manner. Moreover, at higher Ang II concentrations (≥1 µmol/l), no significant increase in O2 generation was reported in HUVEC, indicating an enhanced availability of NO and supporting our results that, at higher doses, Ang II exhibits beneficial vascular effects (42).…”

Fatores e mecanismos envolvidos na hipertrofia ventricular esquerda e o papel anti-hipertrófico do óxido nítrico

“…Several physiopathological and genetic situations can induce cardiac oxidative stress, such as the increase in the concentration of AngII 31 , hypercholesteremia 32 , mechanical stress in the myocardium 33 and inflammatory processes 34 .…”