Abstract 3578: Angiotensin II Induced Muscle Wasting is Redox Dependent: Differential Requirement of p47 phox in the Anorexigenic and Catabolic Effects of Angiotensin II
Advanced congestive heart failure (CHF) is characterized by increased angiotensin II (ANG) and anorexia/cachexia. ANG induces vascular oxidative stress, primarily via activation of NADPH oxidase. We have previously shown that ANG infusion in mice causes marked skeletal muscle wasting via a reduction in appetite and a catabolic effect. To determine the role of oxidative stress, FVB mice were infused with 1 μg/kg/min ANG or vehicle (SHM) for 7 d with/without an oral antioxidant (N-acetyl-L-cysteine, NAC, 1%). ANG decreased skeletal muscle weight in FVB (ANG/SHM, gastrocnemius: 100.2±1.7/122.5±2.9 mg; tibialis anterior: 32.6±1.3/42.7±1.0mg; quadriceps: 122.6±3.5/161.4±4.8 mg; n=7; p<0.05 in each case), and this effect was markedly inhibited by NAC (ANG+NAC/SHM+NAC, gastrocnemius: 111.6±3.1/115.5±2.2 mg; tibialis anterior: 35.6±2.2/40.5±1.0mg; quadriceps: 143.9.6±6.0/156.7±3.3mg ; n=7; p=NS). NAC did not alter blood pressure. ANG reduced food intake (mean food intake: ANG 4.6±0.4 g/d vs. SHM 6.6±0.4 g/d, p<0.01) and this was completely prevented by NAC (ANG+NAC 7.2±0.3 g/d vs SHM+NAC: 6.0±0.1 g/d, p=NS). To determine potential involvement of NADPH oxidase, p47 phox null mice and wild-type (WT) littermates were infused with ANG or vehicle. ANG reduction of skeletal muscle weight in WT (ANG/SHM, gastrocnemius: 118.9±2.3/146.5±5.1 mg; tibialis anterior: 35.7±1.8/45.4±1.7mg; n=7; p<0.05) was markedly inhibited in p47 phox null mice (ANG/SHM: gastrocnemius 110.1±4.6 g/124.5 + 5.1g; tibialis anterior: 35.5±1.6 g/38.26±2.1 g; n=7; p=NS). Pair-feeding experiments indicated that the catabolic effect of ANG in WT was not reduced in p47 phox null mice (WT, 2.3±0.8 g body weight loss at 7d ANG vs. pair-fed sham; p47 phox null, 2.0±0.5 g body weight loss at 7d ANG vs. pair-fed sham; p=NS). However the ANG reduction in appetite in WT was completely inhibited in p47 null mice (mean food intake, WT: ANG 4.7±1.3 g/d vs. SHM 9.1±0.6 g/d, p<0.05; p47 phox null: ANG 5.9±0.9 g/d vs SHM 7.2±0.4 g/d, p=NS). In summary, ANG induced muscle wasting is redox dependent and results from anorexigenic and catabolic effects that are p47 phox dependent and independent respectively. Our findings have important implications for understanding mechanisms of anorexia/cachexia in CHF.