Abstract
Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein β-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1, and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/β-Klotho–PI3K–Akt1–BAD signaling network.
Highlights
Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia
As fibroblast growth factor 21 (FGF21) interacts with all known protein tyrosine kinase-coupled FGF receptors (FGFRs), including FGFR1, FGFR2, FGFR3, and FGFR432,36,37, we tested the expression of these FGFRs in cardiomyocytes from wild-type mice with and without myocardial ischemia/reperfusion injury
These observations suggested that FGFR1 and FGFR3 were candidate receptors for FGF21, and b-Klotho was possibly involved in FGF21–FGFR interaction in myocardial ischemia/reperfusion injury
Summary
Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein b-Klotho, inducing FGFR1 phosphorylation This action caused phosphorylation of the signaling molecules PI3K p85, Akt[1], and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. Further tests demonstrated that the FGFR cofactor bKlotho was expressed at a basal level in the cardiomyocyte of healthy mice, and increased in expression from 1 to 5 days and returned to about the basal level at 10 days following myocardial injury (Fig. 2B) These observations suggested that FGFR1 and FGFR3 were candidate receptors for FGF21, and b-Klotho was possibly involved in FGF21–FGFR interaction in myocardial ischemia/reperfusion injury. We intended to test the hypothesis that FGF21 protects cardiomyocytes from injury via the mediation of the FGFRs/b-Klotho–PI3K– Akt1–BAD signaling network in myocardial ischemia/reperfusion injury
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