Abstract 13509: Cardioprotective Role of Ischemia-Induced Trefoil Factor 3
Myocardial ischemia causes cardiomyocyte death, resulting impairment of cardiac function. As cardiomyocyte death is the principal cause of cardiac functional deficits, a potential treatment is to minimize cardiomyocyte death post MI. The goal of this investigation is to test the cardioprotective effect of trefoil factor 3 (TFF3), a secreted protein originally identified in the intestinal epithelium. In myocardial ischemia induced by LAD coronary artery ligation in the mouse, the liver exhibited a 6 and 19-fold increase in the relative mRNA level of TFF3 at day 0.5 and 10 post MI, respectively, in association with an increase in the TFF3 protein level in hepatocytes and the serum. In TFF3-/- mice, the fraction of myocardial infarcts (32.5+/-6.4% with reference to the total LV wall volume, n=6) was significantly larger than that in wildtype mice (25.3+/-3.5%, n=6, p<0.02) at day 1 post MI. Administration of recombinant TFF3 to TFF3-/- mice post MI (50 ng/gm, IV, twice/day) resulted in a significant reduction in the fraction of myocardial infarcts (16.7+/-3.9% at day 1, n=6, p<0.001) in association with significantly improved LV dp/dt. It was further demonstrated that TFF3 administration to normal mice induced phosphorylation of PI3K p85 alpha, Akt1, and BAD in cardiomyocytes within 30 min (n=3). These molecules were also phosphorylated in the ischemic cardiomyocytes of wildtype mice at 1 day post MI (n=4), whereas the relative phosphorylation level of these molecules was reduced in the cardiomyocytes of TFF3-/- mice (n=4) in association with increased myocardial infarcts. Injection of PI3K p110 alpha siRNA to the LV anterior wall of wildtype mice at 6 locations about 2 mm apart 3 days prior to MI (diffusion range of FITC-siRNA tested by fluorescence microscopy) resulted in a reduction in the protein level of PI3K p110 alpha by 63+/-12% (n=5) within the region of siRNA injection at 1 day post MI, in association with a decrease in BAD phosphorylation and an increase in the fraction of myocardial infarcts by 6.5+/-1.6% (compared to mice with injection of scrambled siRNA, p<0.05). These observations suggest that TFF3 is upregulated in the liver in response to myocardial ischemia and contributes to myocardial protection possibly via the PI3K-Akt1-BAD signaling mechanisms.
- © 2011 by American Heart Association, Inc.