Abstract 781: Statin Reverses the Reduction of Adiponectin Receptor Expression in Post-infarct Mouse Myocardium and in TNFα-treated Cardiomyocytes in Association with Improvement of Glucose Uptake
Cardiac insulin resistance after myocardial infarction (MI) is related to myocardial dysfunction. Statin treatment is shown to improve insulin resistance in skeletal muscle of diabetic animals. We have recently shown that myocardium expresses AdipoR1 and AdipoR2, receptors of adiponectin (Adipo) that enhances insulin sensitivity. Thus, this study assessed the hypothesis that statin may affect the expression of AdipoR1/R2 in post-infarct myocardium, leading to improvement of post-MI myocardial insulin resistance.
Methods and Results: MI was made by ligation of the LAD in male C57BL/6J mice (10 wk old). AdipoR1 mRNA expression was decreased in the remote area as well as the healed infarcted area in the left ventricles 4 weeks after MI by 50% and 48 %, respectively, compared to sham-operated ventricle. AdipoR2 mRNA was not significantly changed. Also, protein expression of AdipoR1 and AdipoR2 was similar to mRNA expression. Oral administration of pravastatin (daily dose of 50 mg/kg for 4 weeks after MI) reversed the decrease in AdipoR1 mRNA and protein expression levels in both the remote area and the infarcted area at 4 weeks after MI independently of changes in serum cholesterol and insulin levels, while AdipoR2 expression was not changed. Incubation of cultured cardiomyocytes, with TNFα (100 ng/ml) or norepinephrine (100 nM), mediators of post-infarct myocardial dysfunction, inhibited mRNA and protein expression levels of AdipoR1 (by 67% and 78% in mRNA, by 45% and 58% in protein, respectively). Co-incubation of the cells with pravastatin (≥ 1 μM) reversed the inhibitory effects of TNFα and norepinephrine on AdipoR1 expression. In parallel, pravastatin reversed the decrease in globular Adipo (0.25 μg/ml)-induced 2-deoxy-d-[3H] glucose uptake under basal and insulin-stimulated conditions in the TNFα-treated cells, which was inhibited by the suppression of AdipoR1 expression by siRNA specific for AdipoR1.
Conclusions: Pravastatin treatment reverses the reduction of AdipoR1 expression in the post-infarct myocardium, which may potentially improve myocardial insulin resistance. The reversal effect of pravastatin on AdipoR1 expression in post-infarct myocardium may represent an additional mechanism for the beneficial effects of statin in MI.