Abstract
Our previous studies showed that both exogenous and endogenous FGF21 inhibited cardiac apoptosis at the early stage of type 1 diabetes. Whether FGF21 induces preventive effect on type 2 diabetes-induced cardiomyopathy was investigated in the present study. High-fat-diet/streptozotocin-induced type 2 diabetes was established in both wild-type (WT) and FGF21-knockout (FGF21-KO) mice followed by treating with FGF21 for 4 months. Diabetic cardiomyopathy (DCM) was diagnosed by significant cardiac dysfunction, remodeling, and cardiac lipid accumulation associated with increased apoptosis, inflammation, and oxidative stress, which was aggravated in FGF21-KO mice. However, the cardiac damage above was prevented by administration of FGF21. Further studies demonstrated that the metabolic regulating effect of FGF21 is not enough, contributing to FGF21-induced significant cardiac protection under diabetic conditions. Therefore, other protective mechanisms must exist. The in vivo cardiac damage was mimicked in primary neonatal or adult mouse cardiomyocytes treated with HG/Pal, which was inhibited by FGF21 treatment. Knockdown of AMPKα1/2, AKT2, or NRF2 with their siRNAs revealed that FGF21 protected cardiomyocytes from HG/Pal partially via upregulating AMPK–AKT2–NRF2-mediated antioxidative pathway. Additionally, knockdown of AMPK suppressed fatty acid β-oxidation via inhibition of ACC–CPT-1 pathway. And, inhibition of fatty acid β-oxidation partially blocked FGF21-induced protection in cardiomyocytes. Further, in vitro and in vivo studies indicated that FGF21-induced cardiac protection against type 2 diabetes was mainly attributed to lipotoxicity rather than glucose toxicity. These results demonstrate that FGF21 functions physiologically and pharmacologically to prevent type 2 diabetic lipotoxicity-induced cardiomyopathy through activation of both AMPK–AKT2–NRF2-mediated antioxidative pathway and AMPK–ACC–CPT-1-mediated lipid-lowering effect in the heart.
Highlights
Diabetic cardiomyopathy (DCM) was defined as diabetes-induced impairment in the structure and function of the myocardium that was independent of hypertension and coronary artery disease[1,2]
An obvious ratio increase of heart weight (HW) to tibia length (TL) was observed in diabetic mice compared with nondiabetic mice, which represents cardiac hypertrophy (CH) (Fig. 1a)
CH was further confirmed by the increased LV mass (Table S1) and the overexpressed hypertrophic markers (Fig. 1b−d), which was prevented by FGF21 (Fig. 1b−d)
Summary
Diabetic cardiomyopathy (DCM) was defined as diabetes-induced impairment in the structure and function of the myocardium that was independent of hypertension and coronary artery disease[1,2]. Oxidative stress is the initial cellular pathogenesis of DCM1–4, which causes cardiomyocyte injury by triggering apoptosis[5,6]. Yang et al Cell Death and Disease (2018)9:227. Strong evidence indicates that fibroblast growth factor (FGF)[21] protects the heart from lipopolysaccharideinduced inflammation, isoproterenol-induced cardiac hypertrophy (CH), or ischemia–reperfusion-induced cardiac injury via activating antioxidative effects[10,11]. Our previous study demonstrated that FGF21 prevented the early cardiac damage in type 1 diabetic mice (T1DM). Attributed to the inhibition of lipotoxicity-induced cardiac cell apoptosis[12]. FGF21 deficiency enhanced T1DM-induced oxidative stress in the heart[13]. Since oxidative stress is the initial pathogenesis of cardiac cell apoptosis, whether FGF21 can prevent the cardiac cell apoptosis and the subsequent DCM with the mechanism of antioxidation is still unclear
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