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

Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase having multiple functions and consisting of two isoforms, GSK-3alpha and GSK-3beta. Pressure overload increases expression of GSK-3alpha but not GSK-3beta. Despite our wealth of knowledge about GSK-3beta, the function of GSK-3alpha in the heart is not well understood. To address this issue, we made cardiac-specific GSK-3alpha transgenic mice (Tg). Left ventricular weight and cardiac myocyte size were significantly smaller in Tg than in non-Tg (NTg) mice, indicating that GSK-3alpha 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-3alpha 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-3alpha, but not GSK-3beta, inhibited ERK in cultured cardiac myocytes. Knockdown of GSK-3alpha increased ERK phosphorylation, an effect that was inhibited by PD98059, rottlerin, and protein kinase Cepsilon (PKCepsilon) inhibitor peptide, suggesting that GSK-3alpha inhibits ERK through PKC-MEK-dependent mechanisms. Knockdown of GSK-3alpha 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-3alpha. In conclusion, up-regulation of GSK-3alpha 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-3alpha is mediated through inhibition of ERK.

• Authors: Peiyong Zhai, Shumin Gao, Eric Holle, Xianzhong Yu, Atsuko Yatani, Thomas Wagner, Junichi Sadoshima
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 45 Pg. 33181-91 (Nov 09 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17855351 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Ribosomal Protein S6 Kinases, 70-kDa
• Protein Kinase C-delta
• Protein Kinase C-epsilon
• Extracellular Signal-Regulated MAP Kinases
• Glycogen Synthase Kinase 3
• glycogen synthase kinase 3 alpha

Topics

• Animals
• Apoptosis
• Blood Pressure
• Cardiomegaly (metabolism, pathology, physiopathology)
• Cells, Cultured
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Fibrosis (genetics, metabolism, pathology)
• Gene Expression Regulation
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Heart (drug effects, growth & development)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Transgenic
• Phosphorylation (drug effects)
• Protein Kinase C-delta (metabolism)
• Protein Kinase C-epsilon (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)