Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy

Background In the diabetic heart the beta-adrenergic response is altered partly by down-regulation of the beta 1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the beta 3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their pleiotropic effects. The objective of our study was to investigate the role of statin treatment on beta-adrenergic dysfunction in diabetic rat cardiomyocytes. Methods beta-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg(-1).day(-1)). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline +/- SD. Results Atorvastatin restored the impaired positive inotropic effect of beta-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the beta-adrenergic pathway and corrected the protein expression of beta 1-adrenoceptor and beta 1/beta 3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the beta-adrenoceptor response. Conclusions Atorvastatin restored the positive inotropic effect of the beta-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the beta-adrenergic signaling pathway, particularly through the NOS pathway.