Congestive heart failure (CHF) is a leading cause of cardiovascular mortality and morbidity and is associated with elevated circulating levels of angiotensin II (ang II) and muscle wasting, which is an important predictor of poor outcome in patients with this disease. We have shown recently that ang II infusion in rats produces skeletal muscle wasting secondarily to increased muscle proteolysis and increased apoptosis. Since an increase in superoxides mediates proapoptotic and proteolytic effects in different in vitro models, we hypothesized that oxidative stress is associated with ang II-induced muscle wasting. FVB mice were infused with ang II (ANG, 500 ng/kg/min, n = 6) or vehicle (SHM) and were pair fed for 7 days. Ang II decreased weight of gastrocnemius muscles (SHM, 141.8 ±5.9 g vs ANG, 129.8 ± 7.5 g, p < .10, left muscle, wet weight and SHM, 50.3 ± 5.2 g vs ANG, 42.1 ± 2.5 g, p < .05, right muscle, dry weight). Ang II-induced muscle wasting was associated with a 52% increase in total superoxide levels (SHM, 124.4 ± 67 vs ANG, 189.9 ± 44 relative light U/mg protein, p < .05) as measured by L-012-based luminescent assay of the gastrocnemius muscle. Superoxide formation in skeletal muscles from SHM and ANG mice was completely suppressed (by 95 ± 5% and 93 ± 3% compared with the DMSO control, respectively) with 290 μM apocynin, a specific inhibitor of NADPH oxidase (NOX). NOX activation by adding 2 mM NADPH substrate to muscle fragments produced a 3.7-fold greater superoxide burst from ANG muscle samples compared with control, indicating a critical role for NOX in ang II-induced superoxide generation. Ang II increased relative gene expression of two NADPH oxidase subunits: p22phox and p47phox (by 55% and 88%, respectively) as measured with real-time PCR. These findings strongly suggest that ang II activates NADPH oxidase and via this mechanism increases superoxide formation in skeletal muscle. The link between NADPH oxidase, oxidative stress, and ang II effects has widespread clinical implications for understanding the mechanisms of catabolic conditions. Therapeutic interventions targeting crosstalk mechanisms between ang II and NADPH oxidase could provide new approaches for the treatment of muscle wasting and CHF.
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