Abstract
Purpose: Myocardial ischemia activates innate protective mechanisms, enhancing cardiomyocyte tolerance to ischemia. Here, we demonstrate that the liver contributes to myocardial protection by up-regulating and releasing the secretory protein FGF21. Methods: Myocardial ischemia was induced in mice by ligating the LAD coronary artery. Myocardial infarction was assessed by histological assays. Left ventricular function was evaluated by echocardiography and hemodynamic analysis. The expression and activity of FGF21 and signaling molecules, including FGFR1, PI3K, Akt1, and BAD, were tested by immunoprecipitation/immunoblotting. The cardioprotective role of FGF21 was assessed in FGF21−/− and FGF21-Tg (overexpression) mice. The regulatory role of FGFR1, PI3K, and Akt1 was evaluated by siRNA-mediated gene silencing. Results: FGF21 was up-regulated in hepatocytes and serum from 0.5 to 3 days post myocardial ischemia. FGF21-/mice exhibited increased myocardial infarction, whereas FGF21-Tg mice showed reduced myocardial infarction compared to wild-type mice from 1 to 30 days, suggesting a cardioprotective role for FGF21. Administration of recombinant FGF21 to healthy mice or myocardial ischemia induced FGFR1 phosphorylation in cardiomyocytes. FGF21-/mice with myocardial ischemia exhibited reduced phosphorylation of FGFR1, PI3K, Akt1, and BAD in cardiomyocytes. siRNA-mediated FGFR1 gene silencing suppressed FGFR1 expression and reduced phosphorylation of PI3K, Akt1, and BAD, resulting in an increase in myocardial infarction. PI3K or Akt1 gene silencing reduced BAD phosphorylation and enhanced myocardial infarction, suggesting that BAD phosphorylation is required for effective cardioprotection. Conclusions: The liver contributes to myocardial protection by upregulating and releasing FGF21, and FGF21 activates the FGFR1-PI3KAkt1-BAD signaling pathway, enhancing myocardial tolerance to ischemic injury.
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