Abstract 12573: Myocardial Ischemia-Induced Hepatic Fibroblast Growth Factor 21 for Cardioprotection
Myocardial ischemia, while causing cardiomyocyte injury, activates innate protective mechanisms, enhancing cardiomyocyte tolerance to ischemia. Here, we demonstrate that the liver contributes to cardioprotection by upregulating and releasing the secretory protein fibroblast growth factor 21 (FGF21). In mouse myocardial ischemia induced by LAD coronary artery ligation, hepatocytes upregulated FGF21 mRNA by 11 folds at 12 hrs, followed by an increase in the FGF21 protein level in hepatocytes and the serum. FGF21-/- mice exhibited increased myocardial infarction at 1, 5, 10, and 30 days (59+/-7%, 61+/-9%, 53+/-8%, and 45+/-7%, respectively, based on the LV wall volume below the coronary ligation, n=7, ANOVA p<0.001) compared to wildtype mice (48+/-7%, 48+/-8%, 41+/-7%, and 34+/-6%, respectively, n=7), whereas FGF21-Tg (overexpression) mice showed reduced myocardial infarction (32+/-7%, 33+/-6%, 29+/-4%, and 23+/-5%, respectively, n=7, ANOVA p<0.001), suggesting a cardioprotective role for FGF21. Administration of recombinant FGF21 to healthy mice induced co-immunoprecipitation of FGF21 with FGFR1, enhancing phosphorylation of FGFR1, PI3K, Akt1, and BAD in cardiomyocytes from 10 to 90 min. Myocardial ischemia enhanced phosphorylation of FGFR1, PI3K, Akt1, and BAD in cardiomyocytes from 0.5 to 3 days post myocardial ischemia, while their expression levels did not change. FGF21-/- mice exhibited reduced phosphorylation of FGFR1, PI3K, Akt1, and BAD in cardiomyocytes post myocardial ischemia at 1 day. FGFR1 gene silencing by direct siRNA injection into the anterior LV wall at 6 equally spaced locations 3 days before LAD ligation suppressed FGFR1 expression, reduced phosphorylation of PI3K, Akt1, and BAD, and enhanced myocardial infarction at 1 day (from 46+/-7% to 57+/-9, n=7, p<0.05). PI3K or Akt1 gene silencing reduced BAD phosphorylation and enhanced myocardial infarction at 1 day (from 46+/-7% to 59+/-10%, n=7, p<0.02 for PI3K and from 46+/-7% to 61+/-10%, n=7, p<0.01 for Akt1). These observations suggest that the liver contributes to myocardial protection by upregulating and releasing FGF21, and FGF21 activates the FGFR1-PI3K-Akt1-BAD signaling pathway, reducing cardiomyocyte injury in myocardial ischemia.
- © 2012 by American Heart Association, Inc.