Glycogen Synthase Kinase-3β Regulates Growth, Calcium Homeostasis, and Diastolic Function in the Heart

• Published in: The Journal of biological chemistry Vol. 279; no. 20; pp. 21383 - 21393
• Main Authors: Michael, Ashour, Haq, Syed, Chen, Xin, Hsich, Eileen, Cui, Lei, Walters, Brian, Shao, Zhili, Bhattacharya, Kausik, Kilter, Heiko, Huggins, Gordon, Andreucci, Michele, Periasamy, Muthu, Solomon, Robert N., Liao, Ronglih, Patten, Richard, Molkentin, Jeffery D., Force, Thomas
• Format: Journal Article
• Language: English
• Published: 14.05.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M401413200

Glycogen synthase kinase (GSK) 3 beta is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3 beta plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3 beta in the heart has a dramatic impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal cardiac contractile function. The most striking phenotype, however, is grossly impaired diastolic relaxation, which leads to increased filling pressures of the left ventricle and massive atrial enlargement. This is due to profoundly abnormal calcium handling, leading to an inability to normalize cytosolic [Ca super(2+)] in diastole. The alterations in calcium handling are due at least in part to direct down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK-3 beta , acting at the level of the SERCA2 promoter. These studies identify GSK-3 beta as a regulator of normal growth of the heart and are the first of which we are aware, to demonstrate regulation of expression of SERCA2a, a critical determinant of diastolic function, by a cytosolic signaling pathway, the activity of which is dynamically modulated. Deregulation of GSK-3 beta leads to severe systolic and diastolic dysfunction and progressive heart failure. Because down-regulation of SERCA2a plays a central role in the diastolic and systolic dysfunction of patients with heart failure, these findings have potential implications for the therapy of this disorder.