© 2000 American Heart Association, Inc.
Cellular Biology |
Coronary Microvascular Endothelial Cell Redox State in Left Ventricular Hypertrophy
The Role of Angiotensin II
From the Cardiovascular Sciences Research Group, Sir Geraint Evans Wales Heart Research Institute, Department of Pharmacology, Therapeutics, and Toxicology, University of Wales College of Medicine, Cardiff, Wales.
Correspondence to D. Lang, Department of Pharmacology, Therapeutics, and Toxicology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN UK. E-mail langd{at}cf.ac.uk
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 (O2-) 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 O2- production in the particulate fraction of CMVE lysates. In cultured cells, incubation with Ang II (0.1 nmol/L to 1 µmol/L for 18 hours) resulted in significant (P<0.01) increases in both NADH- and NADPH-dependent O2- production, with a peak effect at 1 nmol/L. The latter was significantly (P<0.01) inhibited by the AT1 receptor antagonist losartan (1 µmol/L for 18 hours). In contrast, the O2- response to Ang II (0.1 nmol/L to 1 µmol/L for 18 hours) was largely unaffected by concomitant exposure to the AT2 antagonist PD 123319 (1 µmol/L). In freshly isolated CMVEs from nonoperated animals, NADH- and NADPH-dependent O2- 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 µg/L, n=12) compared with sham-operated animals (0.63±0.06 µg/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 O2- production.
Key Words: NADH/NADPH oxidase • coronary microvascular endothelium • angiotensin II • left ventricular hypertrophy • superoxide anion
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