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.
Highlights
Glycogen synthase kinase-3 (GSK-3) has two isoforms, GSK-3␣ and GSK-3
Our results suggest that GSK-3␣ negatively regulates cardiac growth and promotes apoptosis in cardiac myocytes and that GSK-3␣ is upregulated by clinically important pathologic insults such as pressure overload and myocardial infarction
GSK-3␣ Inhibits Cardiac Myocyte Growth and Promotes hearts and cardiac myocyte size, increases in apoptosis and Apoptosis through Inhibition of extracellular signal-regulated kinases (ERKs)—We examined the fibrosis, and normal cardiac function at base line
Summary
Primary Culture of Neonatal Rat Ventricular Myocytes—Primary cultures of ventricular cardiac myocytes were prepared from 1-day-old Crl: (WI) BR-Wistar rats (Charles River Laboratories, Wilmington, MA) as previously described [18]. Robbins), we made transgenic mice with cardiac-specific expression of GSK-3␣. Ured at the time of the apparent maximal LV diastolic dimen- Briefly, the number of nuclei per unit area of myocardium sion, whereas LV end-systolic dimension was measured at the (N(n)A) was determined in 20 fields (40ϫ). Heart spec- tion N(n)v ϭ N(n)A/Dn. The estimated total number of imens were fixed with 10% neutral-buffered formalin, myocyte nuclei in the left ventricle was calculated as the product of the number of myocyte nuclei per unit volume, N(n)v, and the total ventricular volume, VT, which was derived from the left ventricular weight using the specific gravity of muscle tissue, 1.06 g/ml
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