Abstract 14690: Tnf-a Overproduction in Post-Ischemic Hearts Abolishes the Cardioprotection of Late Insulin Treatment
Background: Previous studies from our lab and others have demonstrated that early insulin treatment protects the heart against acute myocardial ischemia (AMI) injury. However, early insulin treatment is not always available for all the AMI patients. In this study we thus compared the effects of early and late insulin treatment on post-ischemic cardiac funtion and remodeling and the underlying mechanisms.
Methods and Results: Ischemic heart failure was induced by left anterior descending coronary artery occlusion in male SD rats. Early insulin treatment (20 min after MI) improved cardiac function and retarded ventricular remodeling, as evidenced by increased ejection fraction (58.4 ± 3.2% vs. 40.1 ± 2.0% of saline, n=11, P<0.05), less LV dilatation (0.48 ± 0.02 vs. 0.62 ± 0.03 cm of saline, n=11, P<0.05) and interstitial fibrosis. However, there were no significant changes in cardiac function and remodeling between the late insulin-treated (1 week after MI) and saline-treated animals. Interestingly, compared with the sham hearts, insulin-stimulated noninfarcted myocardial fluorodeoxyglucose (FDG) uptake and Akt phosphorylation were significantly reduced at 1 week after MI (Standardized Uptake Value: 16.36 ± 1.81 vs. 43.24 ± 2.45 of sham+insulin, n=6, P<0.01), indicating the declined myocardial insulin sensitivity at this time. Meanwhile, myocardial TNF-α production was increased. Importantly, etanercept, a TNF-α inhibitor, administrated within the first week after MI, not only partly recovered myocardial insulin sensitivity but also restored the cardioprotective effects of late insulin treatment after MI. Moreover, adenovirus-mediated cardiac overexpression of TNF-α resulted in myocardial insulin resistance in non-MI hearts, and further abolished the benefits of early insulin treatment after MI.
Conclusions: These data demonstrate that early insulin treatment improves cardiac function and retards ventricular remodeling in the MI rats. While late insulin treatment at 1 week after MI fails to exert the protective effects due to myocardial insulin resistance induced by TNF-α overproduction.
- © 2013 by American Heart Association, Inc.