GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired beta-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 Inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3alpha appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of beta-adrenergic responsiveness. In the absence of GSK-3alpha, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of beta-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3.