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Activation of AMPK/miR-181b Axis Alleviates Endothelial Dysfunction and Vascular Inflammation in Diabetic Mice
Chak-Kwong Cheng1,2, Wenbin Shang2, Jian Liu3
1Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China.
Abstract:
Hyperglycemia in diabetes mellitus impairs endothelial function and disrupts microRNA (miRNA) profiles in vasculature, increasing the risk of diabetes-associated complications, including coronary artery disease, diabetic retinopathy, and diabetic nephropathy. miR-181b was previously reported to be an anti-inflammatory mediator in vasculature against atherosclerosis. The current study aimed to investigate whether miR-181b ameliorates diabetes-associated endothelial dysfunction, and to identify potential molecular mechanisms and upstream inducer of miR-181b. We found that miR-181b level was decreased in renal arteries of diabetic patients and in advanced glycation end products (AGEs)-treated renal arteries of non-diabetic patients. Transfection of miR-181b mimics improved endothelium-dependent vasodilation in aortas of high fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice, accompanied by suppression of superoxide overproduction and vascular inflammation markers. AMPK activator-induced AMPK activation upregulated miR-181b level in human umbilical vein endothelial cells (HUVECs). Chronic exercise, potentially through increased blood flow, activated AMPK/miR-181b axis in aortas of diabetic mice. Exposure to laminar shear stress upregulated miR-181b expression in HUVECs. Overall, our findings highlight a critical role of AMPK/miR-181b axis and extend the benefits of chronic exercise in counteracting diabetes-associated endothelial dysfunction.
Insights
MicroRNA-181b (miR-181b) protects against diabetes-induced endothelial dysfunction by reducing inflammation and oxidative stress. Chronic exercise and AMPK activation boost miR-181b, offering a therapeutic strategy for diabetic vascular complications.
Area of Science:
- Vascular Biology
- Endocrinology
- Molecular Medicine
Background:
- Diabetes mellitus-induced hyperglycemia impairs endothelial function and increases the risk of vascular complications.
- MicroRNAs (miRNAs) play crucial roles in vascular health, with miR-181b previously identified as an anti-inflammatory mediator.
- Diabetes is associated with altered miRNA profiles, potentially contributing to endothelial dysfunction.
Purpose of the Study:
- To investigate the role of miR-181b in ameliorating diabetes-associated endothelial dysfunction.
- To identify the molecular mechanisms underlying miR-181b's effects.
- To explore upstream inducers of miR-181b in the context of diabetes.
Main Methods:
- Measured miR-181b levels in renal arteries of diabetic patients and advanced glycation end product (AGE)-treated non-diabetic patients.
- Utilized high fat diet (HFD)/streptozotocin (STZ)-induced diabetic mouse models and human umbilical vein endothelial cells (HUVECs).
- Employed miR-181b mimics, AMPK activators, chronic exercise protocols, and laminar shear stress exposure.
Main Results:
- miR-181b levels were decreased in diabetic renal arteries and AGE-treated vessels.
- miR-181b mimic transfection improved endothelium-dependent vasodilation in diabetic mice, suppressing oxidative stress and inflammation.
- AMPK activation and chronic exercise upregulated miR-181b, while laminar shear stress also increased its expression in HUVECs.
Conclusions:
- The AMPK/miR-181b axis plays a critical role in counteracting diabetes-associated endothelial dysfunction.
- miR-181b ameliorates endothelial dysfunction by reducing vascular inflammation and superoxide production.
- Chronic exercise, through AMPK activation, represents a potential therapeutic strategy to enhance miR-181b levels and improve vascular health in diabetes.
