Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve

Aims Impaired Ca2þcycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca2þcycling and excitation–contraction in cardiomyocytes. However, the role of the AKAP150 signalling complexes in the pathogenesis of heart failure has not been investigated. Methods Here we examined how AKAP150 signalling complexes impact Ca2þcycling, myocyte contractility, and heart failure and results susceptibility following pathological stress. We detected a significant reduction of AKAP150 expression in the failing mouse heart induced by pressure overload. Importantly, cardiac-specific AKAP150 knockout mice were predis- posed to develop dilated cardiomyopathy with severe cardiac dysfunction and fibrosis after pressure overload. Loss of AKAP150 also promoted pathological remodelling and heart failure progression following myocardial infarction. However, ablation of AKAP150 did not affect calcineurin-nuclear factor of activated T cells signalling in cardiomyo- cytes or pressure overload- or agonist-induced cardiac hypertrophy. Immunoprecipitation studies showed that AKAP150 was associated with SERCA2, phospholamban, and ryanodine receptor-2, providing a targeted control of sarcoplasmic reticulum Ca2þregulatory proteins. Mechanistically, loss of AKAP150 led to impaired Ca2þcycling and reduced myocyte contractility reserve following adrenergic stimulation or pressure overload.Conclusions These findings define a critical role for AKAP150 in regulating Ca2þcycling and myocardial ionotropy following patho- logical stress, suggesting the AKAP150 signalling pathway may serve as a novel therapeutic target for heart failure.