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FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.

ABSTRACT: Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21's effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild-type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. There was no significant difference between FGF21KO and WT diabetic mice in blood glucose and triglyceride levels. FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodelling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Western blots showed that increased cardiac lipid accumulation was accompanied by further increases in the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein CD36, along with decreases in the phosphorylation of AMP-activated protein kinase and the expression of hexokinase II and peroxisome proliferator-activated receptor gamma co-activator 1? in the heart of FGF21KO diabetic mice compared to WT diabetic mice. Our results demonstrate that FGF21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 up-regulation, which may contribute to the increased cardiac oxidative stress and remodelling, and the eventual development of DCM. These findings suggest that FGF21 may be a therapeutic target for the treatment of DCM.

SUBMITTER: Yan X

PROVIDER: S-EPMC4511354 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.

Yan Xiaoqing X Chen Jun J Zhang Chi C Zhou Shanshan S Zhang Zhiguo Z Chen Jing J Feng Wenke W Li Xiaokun X Tan Yi Y

Journal of cellular and molecular medicine 20150330 7

Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21's effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild-type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. Ther ...[more]

PMID: 25823710

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Project description:BackgroundDiabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD+) redox imbalance; however, the hypothesis that NAD+ redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD+ redox balance to test this hypothesis.MethodsDiabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological, and molecular analyses. Two mouse models with altered NAD+ redox states (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used.ResultsDiabetic stress caused cardiac dysfunction and lowered NAD+/NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD+/NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD+ redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P<0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 1.20, P<0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix-dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD+ redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin I S150 phosphorylation, and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by NAMPT normalized NAD+ redox balance, alleviated cardiac dysfunction (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P<0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P<0.05), and reversed pathogenic mechanisms in diabetic mice.ConclusionsOur results show that NAD+ redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD+ metabolism.

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FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.

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FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation.

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