Glycogen synthase kinase-3α reduces cardiac growth and pressure overload-induced cardiac hypertrophy by inhibition of extracellular signal-regulated kinases

Glycogen synthase kinase-3 ( GSK-3) is a serine/threonine kinase having multiple functions and consisting of two isoforms, GSK-3 alpha and GSK-3 beta. Pressure overload increases expression of GSK-3 alpha but not GSK-3 beta. Despite our wealth of knowledge about GSK-3 beta, the function of GSK-3 alpha in the heart is not well understood. To address this issue, we made cardiac-specific GSK-3 alpha transgenic mice ( Tg). Left ventricular weight and cardiac myocyte size were significantly smaller in Tg than in non-Tg ( NTg) mice, indicating that GSK-3 alpha inhibits cardiac growth. After 4 weeks of aortic banding ( transverse aortic constriction ( TAC)), increases in left ventricular weight and myocyte size were significantly smaller in Tg than in NTg, indicating that GSK-3 alpha inhibits cardiac hypertrophy. More severe cardiac dysfunction developed in Tg after TAC. Increases in fibrosis and apoptosis were greater in Tg than in NTg after TAC. Among signaling molecules screened, ERK phosphorylation was decreased in Tg. Adenovirus-mediated overexpression of GSK-3 alpha, but not GSK-3 beta, inhibited ERK in cultured cardiac myocytes. Knockdown of GSK-3 alpha increased ERK phosphorylation, an effect that was inhibited by PD98059, rottlerin, and protein kinase C epsilon ( PKC epsilon) inhibitor peptide, suggesting that GSK-3 alpha inhibits ERK through PKC-MEK-dependent mechanisms. Knockdown of GSK-3 alpha increased protein content and reduced apoptosis, effects that were abolished by PD98059, indicating that inhibition of ERK plays a major role in the modulation of cardiac growth and apoptosis by GSK-3 alpha. In conclusion, up-regulation of GSK-3 alpha inhibits cardiac growth and pressure overload-induced cardiac hypertrophy but increases fibrosis and apoptosis in the heart. The anti-hypertrophic and pro-apoptotic effect of GSK-3 alpha is mediated through inhibition of ERK.