Coronary microvascular dysfunction in diabetes: Role of HuR

[Speaker] Ayako Makino:1
[Co-author] Rui Si:1, Qian Zhang:1, Makiko Watanabe:1
1:Physiology and Medicine, University of Arizona, USA

Recent studies highlighted that coronary microvascular disease is one of the leading causes of mortality and morbidity in diabetes. However, the molecular mechanisms in which the microvascular in the heart becomes more contractile and the number of capillary density gets less in diabetes are not well understood. In this study, we investigated the role of HuR (ELAV-like protein 1) in the development of coronary microvascular disease in diabetes. HuR is an RNA binding protein that regulates the stability of many RNAs. The protein levels of HuR was significantly decreased in coronary endothelial cells (CECs) isolated from type 2 diabetic mice and in human CECs from type 2 diabetic patients compared to the control CECs. Endothelium-specific HuR knockout (HuRKO) mice exhibited reduced coronary flow velocity reserve (CFVR, an indicator of coronary microvascular function), decreased capillary density in the left ventricle, and attenuated endothelium-derived hyperpolarization (EDH)-dependent relaxation in coronary arteries. A PCR-array using CECs isolated from Wt and HuRKO mice identified 20 genes as a target of HuR. We have extensive research experience in one of 20 genes, connexin 40 (Cx40), and Cx40 mRNA level was significantly decreased in CECs isolated from HuRKO mice. Therefore, we examined HuR-Cx40 interaction and the role of Cx40 in endothelial dysfunction in diabetes. Cx40 predominantly expresses in vascular ECs and regulates EDH-dependent vascular relaxation and angiogenesis. RNA immunoprecipitation confirmed the binding between HuR and Cx40mRNA and it was significantly decreased in diabetes. Cx40 protein expression was significantly lower in CECs in diabetic mice and diabetic patients than the control CECs. Both Cx40 KO mice and diabetic mice exhibited decreased CFVR and capillary density and attenuated EDH-dependent relaxation compared to their controls. Cx40 overexpression increased tube formation in high-glucose treated CECs toward the level seen in control CECs. EC-specific Cx40 overexpression significantly increased CFVR in diabetic mice. These data suggest that decreased HuR expression leads to downregulation of Cx40, decreases EDH-dependent relaxation and capillary density, and subsequently reduces CFVR in diabetic mice. Overexpression of HuR and/or Cx40 would be a potential treatment for coronary microvascular disease in diabetes.
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