HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Diabetes Research

Background:

• Diabetic patients with coronary microvascular disease (CMD) face higher cardiac mortality.
• The molecular mechanisms linking diabetes to CMD remain unclear.
• RNA-binding protein HuR regulates mRNA stability and translation.

Purpose of the Study:

• To investigate the role of HuR in the development of CMD in a mouse model of type 2 diabetes.
• To explore the molecular pathways involving HuR in diabetic cardiac endothelial cells.

Main Methods:

• Compared coronary flow velocity reserve (CFVR) and capillary density in diabetic and control mice.
• Assessed HuR levels in cardiac endothelial cells (CECs) from diabetic and control mice and patients.
• Utilized endothelial-specific HuR knockout (KO) mice and Cx40 KO mice.
• Analyzed mRNA levels of 92 genes related to endothelial function.

Main Results:

• Diabetic mice showed reduced CFVR and left ventricular capillary density.
• HuR levels were significantly lower in CECs of diabetic mice and patients.
• Endothelial-specific HuR-KO mice exhibited decreased CFVR and capillary density.
• HuR, Cx40, and Nox4 levels were reduced in CECs from diabetic and HuR-KO mice.
• HuR binding to Cx40 mRNA and Cx40 expression were downregulated in diabetic CECs.
• Cx40-KO mice had reduced CFVR and capillary density; Cx40 overexpression improved these parameters in diabetic mice.

Conclusions:

• Decreased HuR in cardiac endothelial cells contributes to CMD development in diabetes.
• This occurs via the downregulation of the gap junction protein Cx40.
• HuR-mediated regulation of Cx40 is a key pathway in diabetic coronary microvascular dysfunction.