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

Abstract

Glycogen synthase kinase (GSK) 3␤ is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3␤ plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3␤ 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 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␤, acting at the level of the SERCA2 promoter. These studies identify GSK-3␤ 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. De-regulation of GSK-3␤ 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.

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

“…ANT, VDAC, CypD). Moreover, we cannot fully exclude a contribution of SERCA2 since Michael et al 12 previously demonstrated that overexpression of GSK3β could significantly reduce the expression of SERCA2 in the heart. 12 We noticed in the present work that SERCA2 expression seems to be increased when GSK3β was inhibited at the onset of reperfusion (data not shown).…”

“…Moreover, we cannot fully exclude a contribution of SERCA2 since Michael et al 12 previously demonstrated that overexpression of GSK3β could significantly reduce the expression of SERCA2 in the heart. 12 We noticed in the present work that SERCA2 expression seems to be increased when GSK3β was inhibited at the onset of reperfusion (data not shown). Such mechanism remains to be investigated in-depth in future studies, especially since a problem of timing has to be considered between the speed of Ca 2+ response and the time needed for SERCA2 protein transcription at the onset of reperfusion.…”

“…It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells. 10,11 GSK3β also has other proposed mechanisms of action, including a poorly characterized role in calcium (Ca 2+ ) homeostasis regulation 12 and protein-protein interactions, 9 as well as functions in different subcellular fractions such as the nucleus, cytosol and mitochondria. 13 Reperfusion is the most powerful intervention to salvage ischemic myocardium.…”

Cardiac-specific haploinsufficiency of β-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction

“…GSK-3β is a well-characterized regulator of cytoplasmic β-catenin level. Recent study has shown that cardiac overexpression of wild type GSK-3β inhibits postnatal physiological growth [6]. The deficiency in cardiac growth lies in the defect of cardiac myocytes to growth in cell diameter, while myocyte growth in length is maintained or even enhanced.…”

“…Constitutively active GSK-3β attenuates cardiac hypertrophy by phosphorylating the nuclear factor of activated T cells (NFAT) and inhibiting its nuclear translocation. Similarly, the overexpression of wild-type GSK-3β in the heart also inhibits cardiac hypertrophy [5], most likely through the reduction of cytoplasmic β-catenin levels in cardiac myocyte [6]. Interestingly, wild-type GSK-3β also inhibits postnatal physiological growth in addition to pathological hypertrophy.…”