Abstract 14068: Differential Requirement For NADPH Oxidase- And Mitochondria-Derived Superoxides in Angiotensin II-Induced Skeletal Muscle Wasting (Cachexia) and Blood Pressure Increase
The renin-angiotensin system (RAS) is important for volume and blood pressure regulation and in cardiovascular and renovascular disease; however angiotensin II (ANG) effects on skeletal muscles are poorly understood. We have previously shown that ANG infusion in mice reduced lean body mass (cachexia) and this effect correlated with increased muscle reactive oxygen species (ROS) levels. We determined whether cachexia is mediated by an increase in ROS and evaluated the role of NADPH oxidase (Nox) and mitochondria in ANG-induced muscle atrophy and hypertension. C57BL/6 (WT) mice were treated with the antioxidant N-acetylcysteine (NAC) and infused with ANG (1 ug/kg/min) or vehicle (Sham) for 7d. ANG induced gastrocnemius skeletal muscle weight loss (16.7±2.3% reduction vs. Sham, n=30, P<0.05) and increased muscle ROS levels (oxidized/reduced glutathione ratio, GSSG/GSH assay, 3.6±0.5-fold increase, P<0.05;DHE assay, 2.9±0.2-fold increase, P<0.05) and NAC blocked these effects. NAC had no effect on ANG-increased blood pressure. WT mice or mice deficient for p47phox, a key Nox subunit (P47 mice) were infused with ANG or Sham (n=30). ANG-induced cachexia was partially reduced (34% inhibition of muscle loss, P<0.05) and the ROS increase was completely blocked in P47 mice as assessed by GSSG/GSH and DHE assay. ANG-induced hypertension was not altered by p47phox deficiency. WT mice were co-infused with ANG or Sham and with the mitochondrial superoxide-specific blocker MitoTEMPO (0.4 ug/kg/min). MitoTEMPO did not alter ANG-induced total superoxides (DHE assay) and reduction in skeletal muscle weight. However, MitoTEMPO completely blocked ANG-dependent mitochondrial superoxides (MitoSOX assay) and partially reduced the blood pressure increase (ANG + MitoTEMPO: systolic blood pressure, 145±7 vs. ANG: 164±9 mmHg, P<0.05) indicating that mitochondrial ROS were involved in the hypertensive but not the cachectic response to ANG. In summary, NADPH oxidase-derived ROS play the predominant role in ANG-induced oxidant signaling leading to muscle atrophy whereas mitochondria-derived ROS are critical for mediating the hypertensive response to ANG.
- © 2011 by American Heart Association, Inc.