Abstract 544: Glycogen Synthase Kinase-3α Regulates Cardiac Growth and Attenuates Pressure Overload-induced Cardiac Hypertrophy in Transgenic Mice
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase having multiple functions including growth, death and metabolism. Two isoforms of GSK-3, GSK-3α and GSK-3β, have been identified in myocardium. The function and signaling mechanisms of GSK-3α in the heart are not well understood. We therefore generated cardiac-specific GSK-3α expression transgenic mice (Tg). GSK-3α was overexpressed by 4.3-fold while expression of GSK-3β was decreased by 76% compared to non-transgenic (NTg) (line 28). At 10 weeks, left ventricular weight (LVW)/tibia length (TL) was significantly lower in Tg than in NTg (3.64±0.18 vs 4.39±0.17, p<0.05). Tg had slightly smaller cardiac myocyte size than NTg (1.00±0.01vs 0.89±0.01, p<0.05), suggesting that GSK-3α negatively affects cardiac physiological growth. After 4 weeks of transverse aortic banding (TAC), the LV of Tg was significantly smaller than that of NTg (LVW/TL, 5.4±0.1 vs 7.3±0.2, p<0.01). Cardiac myocyte size was increased 1.4 fold in NTg, but was 1.2 fold in Tg (p<0.05 Tg vs NTg), suggesting that cardiac hypertrophy is inhibited in Tg. Interestingly, despite attenuation in hypertrophy and normal basal ejection fraction (EF) and fractional shortening (FS), more severe lung congestion (lung weight/TL, 21±1 vs 11±1, p<0.05), reduction in EF and FS (EF, 49±10 vs. 70±1, p<0.01; FS, 21±5 vs 33±1, p<0.01), and more reduction in +dP/dt and −dP/dt (+dP/dt, 4625±382 vs 6900±400, p<0.01; −dP/dt, 4125±629 vs 7600±748, p<0.01) were observed in Tg after TAC. These data indicate that GSK-3α promotes cardiac dysfunction after TAC. More TUNEL positive nuclei were identified in Tg hearts (0.27±0.02% vs 0.15±0.02%, p<0.001), suggesting GSK-3α stimulates apoptosis after TAC. In Tg hearts, ERK, p38, β-catenin, and SERCA-2a were downregulated by 30%, 62%, 65%, and 26%, respectively, while JNK was activated by 1.8 fold. In conclusion, cardiac-specific overexpression of GSK-3α attenuated physiological growth and pressure overload-induced cardiac hypertrophy. GSK-3α increased apoptosis and exacerbated cardiac dysfunction in response to pressure overload in transgenic mice. This is in contrast to a previous report showing well maintained LV function despite inhibition of hypertrophy after TAC in GSK-3β (S9A) transgenic mice.