Abstract 8812: Direct Renin Inhibitor Ameliorates Insulin Resistance by Improving Insulin Signaling in the Skeletal Muscle in Experimental Post-Infarct Heart Failure

Abstract

Background Insulin resistance has been shown to occur as a consequence of heart failure (HF). The activation of renin-angiotensin system may play an important role in this phenomenon. We thus investigated the effects of direct renin inhibitor, aliskiren, on the insulin resistance and the insulin signaling in the skeletal muscle from experimental HF after myocardial infarction (MI). Methods MI was created in male C57BL/6J mice by ligating the left coronary artery, and sham operation was also performed. Mice were divided into 4 groups; sham-operated (sham, n=10), sham treated with aliskiren (10mg/kg/day, n=10), MI (n=10), and MI treated with aliskiren (MI+Ali, n=10). After 4 weeks, echocardiographic and hemodynamic measurements were performed. Plasma glucose levels after intraperitoneal glucose or insulin load were measured. Proteins regulating insulin signaling were measured in the lower extremity skeletal muscle tissues by Western blot analysis. The lucigenin chemiluminescence elicited by •O 2 - and NAD(P)H oxidase activities were also measured in the skeletal muscle. Results Heart rate and aortic blood pressure were not affected by aliskiren in either group. MI mice showed left ventricular (LV) dilatation, dysfunction and an increase in LV end-diastolic pressure, which were not affected by aliskiren. Infarct size was comparable between MI and MI+Ali. Plasma glucose levels at baseline and after glucose load did not differ among groups. However, the decrease in plasma glucose after insulin load was smaller in MI than sham (14±5 vs. 36±2 %, p<0.05), and was significantly ameliorated in MI+Ali (34±5 %, p<0.05). Insulin-stimulated serine-phosphorylation of Akt and the translocation of glucose transporter-4 from cytosol to membrane were decreased in MI by 57 and 69 % of sham, respectively, Aliskiren significantly ameliorated them by 86 and 93 % of sham, respectively. Moreover, •O 2 - production and NAD(P)H oxidase activities were increased in MI and this increase was also inhibited in MI+Ali. Such effects of aliskiren were not observed in sham mice. Conclusions Aliskiren ameliorated insulin resistance associated with HF by improving insulin signaling, at least in part, via the inhibition of NAD(P)H oxidase-induced •O 2 - production in the skeletal muscle.