Jian-Ying Wang

Patients with diabetes with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein human antigen R (HuR) is a key regulator of mRNA stability and translation; therefore, we investigated the role of HuR in the development of CMD in mice with type 2 diabetes. Diabetic mice exhibited decreases in coronary flow velocity reserve (CFVR; a determinant of coronary microvascular function) and capillary density in the left ventricle. HuR levels in cardiac endothelial cells (CECs) were significantly lower in diabetic mice and patients with diabetes than the controls. Endothelial-specific HuR-KO mice also displayed significant reductions in CFVR and capillary density. By examining mRNA levels of 92 genes associated with endothelial function, we found that HuR , Cx40 , and Nox4 levels were decreased in CECs from diabetic and HuR -KO mice compared with control mice. Cx40 expression and HuR binding to Cx40 mRNA were downregulated in CECs from diabetic mice. Cx40 -KO mice exhibited decreased CFVR and capillary density, whereas endothelium-specific Cx40 overexpression increased capillary density and improved CFVR in diabetic mice. These data suggest that decreased HuR contributes to the development of CMD in diabetes through downregulation of gap junction protein Cx40 in CECs.

The intestinal autophagy and barrier function are crucial for maintaining the epithelium homeostasis and tightly regulated through well-controlled mechanisms. RNA-binding proteins (RBPs) and long noncoding RNAs (lncRNAs) modulate gene expression at the posttranscription level and are intimately involved in different physiological processes and diverse human diseases. In this review, we first highlight the roles of several RBPs and lncRNAs in the regulation of intestinal epithelial autophagy and barrier function, particularly focusing on the emerging evidence of RBPs and lncRNAs in the control of mRNA stability and translation. We additionally discuss recent findings that the interactions between RBPs and lncRNAs alter the fate of their target transcripts and thus influence gut epithelium host defense in response to stressful environments. These exciting advances in understanding the posttranscriptional control of the epithelial autophagy and barrier function by RBPs and lncRNAs provide a strong rationale for developing new effective therapeutics based on targeting RBPs and/or lncRNAs to preserve the intestinal epithelial integrity in patients with critical illnesses.