Endocrine Protection of Ischemic Myocardium by FGF21 from the Liver and Adipose Tissue

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.

Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway

“…The present study implies that the prevention of palmitate-induced cardiac apoptosis by FGF21 may partially depend on Akt. Our findings not only support previous studies showing that FGF21-mediated cardiac protection against ischaemia/ reperfusion injury is mediated by PI3K/Akt cell survival signalling under both in vitro and in vivo conditions [18,19], but also further establish FGF21-mediated cardiac protection against diabetic pathogenic changes via upregulation of ERK1/2-p38 MAPK-AMPK-mediated cell survival pathways.…”

“…Here, we provide direct evidence for the anti-apoptotic effect of FGF21 in cardiac tissue, with protection against palmitate in the cultured cardiac cell line and primary cardiomyocytes and STZ-induced diabetes or NEFA infusion in mice. We have also demonstrated that FGF21 supplementation prevents the progression of diabetes-induced cardiomyopathy in both WT and Fgf21-KO mice, a finding that is supportive of previous studies showing FGF21 protects against myocardial ischaemia/reperfusion injury [18,19] and isoprenalineinduced cardiac hypertrophy [20].…”

“…Based on our in vitro studies showing that FGF21 protects against palmitate-induced cardiac apoptosis in H9c2 cells and primary cardiomyocytes, and also previous reports indicating that liver-and adipose-tissue-secreted FGF21 protects the heart from ischaemia/reperfusion injury [18] and exogenous FGF21 protects the heart from isoprenaline-induced cardiac hypertrophy [20], we presume that cardiac protection from diabetes by FGF21 may predominantly be attributed to its direct actions on the heart. The present study elucidated the intracellular mechanisms by which FGF21 prevents palmitate-mediated apoptosis in vitro and NEFA-infusion-or diabetes-mediated apoptosis [35][36][37].…”

“…The existence of FGFR1, β-Klotho [17] and FGF21 [11] in the myocardium implies that FGF21 may play certain physiological roles in the heart. Recently, several studies have demonstrated FGF21-mediated protection against myocardial ischaemia/ reperfusion injury [18,19] and isoprenaline-induced cardiac hypertrophy [20]. However, the effect of FGF21 on diabetic heart remains elusive.…”

Role of Circulating Fibroblast Growth Factor 21 Measurement in Primary Prevention of Coronary Heart Disease Among Chinese Patients With Type 2 Diabetes Mellitus

“…In response to myocardial ischemia in mice, both hepatic and adipocyte‐derived FGF21 expression and secretion were shown to be upregulated, highlighting a cardioprotective response of FGF21 in an endocrine manner 33. Recently, both cardiac FGF21 expression and secretion were also found to be increased significantly with isoproterenol treatment in mice and phenylephrine treatment in neonatal cardiomyocytes, respectively 30.…”