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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Fibroblast growth factor 21 Ameliorates diabetes-induced endothelial dysfunction in mouse aorta via activation of the
Lei Ying1, Na Li1,2, Zhengyue He1,3
1Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China.
Abstract:
Endothelial dysfunction initiates and exacerbates hypertension, atherosclerosis and other cardiovascular complications in diabetic mellitus. FGF21 is a hormone that mediates a number of beneficial effects relevant to metabolic disorders and their associated complications. Nevertheless, it remains unclear as to whether FGF21 ameliorates endothelial dysfunction. Therefore, we investigated the effect of FGF21 on endothelial function in both type 1 and type 2 diabetes. We found that FGF21 reduced hyperglycemia and ameliorated insulin resistance in type 2 diabetic mice, an effect that was totally lost in type 1 diabetic mice. However, FGF21 activated AMPKα, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of aorta in both types, suggesting a mechanism that is independent of its glucose-lowering and insulin-sensitizing effects. In vitro, we identified a direct action of FGF21 on endothelial cells of the aorta, in which it bounds to FGF receptors to alleviate impaired endothelial function challenged with high glucose. Furthermore, the CaMKK2-AMPKα signaling pathway was activated to suppress oxidative stress. Apart from its anti-oxidative capacity, FGF21 activated eNOS to dilate the aorta via CaMKK2/AMPKα activation. Our data suggest expanded potential uses of FGF21 for the treatment of vascular diseases in diabetes.
Insights
Fibroblast Growth Factor 21 (FGF21) improves blood vessel function in both type 1 and type 2 diabetes by activating the CaMKK2-AMPKα pathway. This hormone combats oxidative stress and enhances vasodilation, offering potential for treating diabetic vascular diseases.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Metabolic Disorders
Background:
- Endothelial dysfunction is a key factor in cardiovascular complications associated with diabetes mellitus.
- Fibroblast Growth Factor 21 (FGF21) is known for its metabolic benefits, but its role in endothelial function is not well understood.
Purpose of the Study:
- To investigate the effects of FGF21 on endothelial function in mouse models of type 1 and type 2 diabetes.
- To elucidate the underlying molecular mechanisms of FGF21's action on the vasculature.
Main Methods:
- Administration of FGF21 to type 1 and type 2 diabetic mice.
- In vitro studies on isolated aortic endothelial cells.
- Analysis of the CaMKK2-AMPKα signaling pathway and endothelial nitric oxide synthase (eNOS) activation.
Main Results:
- FGF21 reduced hyperglycemia and insulin resistance in type 2 diabetes, but not type 1.
- FGF21 activated AMPKα in both types of diabetes, suppressing oxidative stress and improving vasorelaxation.
- FGF21 directly acted on endothelial cells, alleviating high glucose-induced dysfunction via the CaMKK2-AMPKα pathway and activating eNOS.
Conclusions:
- FGF21 ameliorates endothelial dysfunction in diabetes through mechanisms independent of its glucose-lowering effects.
- Activation of the CaMKK2-AMPKα pathway and subsequent eNOS activation are crucial for FGF21's vascular protective actions.
- FGF21 shows promise as a therapeutic agent for diabetic vascular complications.
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