Abstract 1575: Disrupted Sarcolemmal nNOS Signaling Leads To Increased L-type Ca2+ Current and Increased Basal Cardiac Function In α-Dystrobrevin Knockout Mice
α-Dystrobrevin, a component of dystrophin-glycoprotein complex (DGC), plays a signaling role by anchoring sarcolemmal nNOS. In this study, we aimed to explore the functional impact of disrupted DGC-mediated nNOS signaling in mice.
Methods: 2~3 month α-dystrobrevin deficient mice (adbn−/−) and wild-type littermates (WT) were characterized at baseline and during β-adrenergic stimulation. Myocyte shortening, Ca2+ transients and Ca2+ currents through L-type Ca2+ channel (ICa) were assessed in isolated ventricular myocytes. Circumferential shortening (CS), an index of in vivo ventricular function, was measured by MRI tagging.
Results: Increased myocyte shortening (11.1±1.7% vs 9.6±2.1%, P<0.01), Ca2+ transients (0.32±0.10 vs 0.27±0.05, P<0.05) and ICa at −10 and −20 mV (Fig.⇓) were observed in isolated myocytes of adbn−/− mice at baseline, leading to increased in vivo ventricular function. CS for adbn−/− and WT mice was 15±1% and 13±1% at midventricle (P<0.05), 13±2% and 11±2% at base (P<0.05). During β-adrenergic stimulation (100nM isoproterenol), similar myocyte shortening (17.0±3.1% vs 17.7±3.5%), Ca2+ transients (0.71±0.13 vs 0.67±0.13) and ICa (1μM isoproterenol, Fig.⇓) were observed between adbn−/− and WT mice. In vivo response to dobutamine (40 μg/kg/min) was also similar. CS was 16±1% vs 15±1% at mid-ventricle, and 13±2% vs 13±2% at base (P=NS).
Conclusion: α-dystrobrevin deficiency led to enhanced basal cardiac function but similar response to β-adrenergic stimulation. Functional enhancement at baseline is associated with increase in L-type Ca2+ influx, suggesting sarcolemma-associated nNOS as a key player in regulating ventricular contractility.