GSK-3α Limits Ischemic Injury, Cardiac Rupture, Post- Myocardial Infarction Remodeling and Death
Background—The molecular pathways that regulate the extent of ischemic injury and post-MI remodeling are not well understood. We recently demonstrated that GSK-3α is critical to the heart's response to pressure overload. However, the role, if any, of GSK-3α in regulating ischemic injury and its consequences is not known.
Methods and Results—MI was induced in wild-type (WT) vs. GSK-3α(-/-) (KO) littermates by LAD ligation. Pre-MI, WT and KO hearts had comparable chamber dimensions and ventricular function, but as early as one week post-MI, KO mice had significantly more LV dilatation and dysfunction than WT. KO mice also had increased mortality during the first 10 days post-MI (43% vs 22%; P=0.04), and post-mortem examination confirmed cardiac rupture as the cause of most of the deaths. In the mice that survived the first 10 d, LV dilatation and dysfunction remained worse in the KO throughout the study (8 wks). Hypertrophy, fibrosis, and heart failure were all increased in the KO. Given the early deaths due to rupture and the significant reduction in LV function evident as early as 1 wk post-MI, we examined infarct size following a 48h coronary artery ligation and found it to be increased in the KO. This was accompanied by increased apoptosis in the border zone of the MI. This increased susceptibility to ischemic injury-induced apoptosis was also seen in cardiomyocytes isolated from the KO that were exposed to hypoxia. Finally, Bax translocation to the mitochondria and cytochrome C release into the cytosol were increased in the KO.
Conclusion—GSK-3α confers resistance to ischemic injury at least in part via limiting apoptosis. Loss of GSK-3α promotes ischemic injury, increases risk of cardiac rupture, accentuates post-MI remodeling and LV dysfunction, and increases the progression to heart failure. These findings are in striking contrast to multiple prior reports in which deletion or inhibition of GSK-3β is protective.
- Received June 18, 2011.
- Accepted November 2, 2011.
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