Abstract 1584: Inhibition of Endogenous GSK-3β Attenuates Cardiac Dysfunction after Myocardial Infarction
Inhibition of glycogen synthase kinase-3β (GSK-3β), a negative regulator of cardiac hypertrophy, is protective during ischemia/reperfusion injury. Whether or not chronic inhibition of GSK-3β is protective during cardiac remodeling after myocardial infarction (MI) is unknown. We addressed this issue using transgenic mice with cardiac specific expression of dominant negative GSK-3β (GSK-3β-DN, Tg), in which the activity of endogenous GSK-3β is suppressed. The left coronary artery was permanently ligated, and the size of MI was similar between Tg and non-transgenic (NTg) mice at days 3 and 28. Tg developed compensated cardiac hypertrophy at baseline. After 4 weeks of MI, however, no additive enhancement of hypertrophy was observed in Tg, indicating that cardiac remodeling after MI shares signaling mechanisms with hypertrophy induced by inhibition of GSK-3. Interestingly, LV ejection fraction was significantly greater in Tg than in NTg (60 vs 50%), whereas LV end-diastolic pressure (8.1 vs 11.3 mmHg) and lung weight/TL (10.6 vs 13.8) were significantly lower in Tg. LV +dP/dt (mmHg/s) was decreased by 16% in Tg (10143±663 to 8375±475) but was decreased significantly more, 24%, in NTg (8200±860 to 6200±627). These data indicate that Tg developed less severe cardiac dysfunction after MI. The amount of interstitial fibrosis in the remodeling area was significantly less in Tg than in NTg (4% vs 7%), although there was no significant difference at baseline. The percentage of TUNEL positive nuclei was not significantly different between Tg and NTg after MI, suggesting the protective effects of GSK-3 inhibition are exerted through apoptosis-independent mechanisms. Periodic acid-Schiff staining revealed significantly more glycogen deposition in the remodeling area of Tg. The number of LC3 dots was significantly less in GSK-3β-DN than in NTg mice (7 vs. 27) 6 days after coronary ligation, indicating that autophagy was attenuated by GSK-3β-DN. In summary, inhibition of GSK-3β failed to show additive effects upon cardiac hypertrophy after MI. Furthermore, inhibition of GSK-3β ameliorates cardiac dysfunction after MI, possibly by preserving glycogen and inhibiting autophagy in cardiac myocytes. In conclusion chronic inhibition of GSK-3β after MI is protective.
This research has received full or partial funding support from the American Heart Association, AHA National Center.