Abstract 13385: Protective Effect of Beta3-Adrenergic Receptor Deficiency on Diabetic Cardiomyopathy: Reversal of Type 2 Diabetes-Induced Contrast Changes of Cardiac SERCA 2a and Inducible Nitric Oxide Synthase

Abstract

Background: We have shown that diabetes (DM)-induced cardiac dysfunction and β-adrenergic desensitization were prevented in β 3 -adrenergic receptor (AR) knockout (β 3 KO) mice. However, the molecular mechanism is unclear. We hypothesize that reversal of type 2 (T2) DM-induced alterations of cardiac SR Ca 2+ -ATPase (SERCA2a) and inducible nitric oxide synthase (iNOS) by β 3 KO may play a key role for the protective effect. Methods: LV myocyte protein levels of β 1 - and β 3 -AR, SERCA2a and iNOS, myocyte contractile and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to isoproterenol (ISO, 10 -8 M) were compared in 4 groups (n=6) female mice: 2 Vehicle controls wild-type (CWT) and Cβ 3 KO; and 2 T2DM of T2WT and T2β 3 KO.T2 was induced by fed high-fat diet (HFD) for 14 weeks (W), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. for 5 days). Results: Mice-treated with HFD plus STZ had high blood glucose (~350 to 380 mg/dl). Versus CWT, T2WT myocytes had significantly decreased protein levels of SERCA2a (0.18 vs 0.29), and β 1 -AR (0.35 vs 0.49), but increased iNOS (0.25 vs 0.15) and β 3 -AR (0.25 vs 0.14) with reduced cell contraction (dL/dt max ) (72.7 vs 140.9 μm/s), relaxation (dR/dt max ) (50.9 vs 117.3 μm/s) and [Ca 2+ ] iT (0.16 vs 0.22). Moreover, in T2WT myocytes, ISO caused significantly less increases in dL/dt max (37% vs 59%), dR/dt max (30% vs 53%) and [Ca 2+ ] iT (19% vs 30%). Versus CWT, T2β 3 KO did not alter basal myocyte contraction and relaxation and response to ISO stimulation, but had significantly increased protein levels of SERCA2a (0.38 vs 0.29). T2β 3 KO prevented DM-caused increase in iNOS (T2β 3 KO: 0.16 vs CWT: 0.15) and decrease in β 1 -AR (0.46 vs 0.49). Versus T2β 3 KO, Cβ 3 KO mice had similar alterations. Importantly, in contrast to T2WT, in T2β 3 KO myocytes, the increased SERCA2a and reduced iNOS correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated inotropic response. ISO caused similar increases in dL/dt max (60% vs 59%), dR/dt max (51% vs 53%) and [Ca 2+ ] iT (32% vs 30%). Conclusions: β 3 KO prevents T2DM-caused downregulation of cardiac β 1 -ARs and reverses increased iNOS and decreased SERCA2a, leading to the preservation of myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve. Thus, β 3 -AR may provide a new target for DCM.