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

Abstract

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.

Restoration of coronary microvascular function by OGA overexpression in a high-fat diet with low-dose streptozotocin-induced type 2 diabetic mice

“…Coronary microvascular function was determined by assessment of coronary flow velocity reserve (CFVR). 14,16 Coronary blood flow velocity (CFV) was measured by echocardiography using a Vevo2100 system (FUJIFILM Visual Sonics, Inc., Toronto, Canada). Mice were anesthetized with isoflurane (1%), and the resting level of CFV was obtained.…”

RNA‐binding proteins in diabetic microangiopathy

“… 34 Associations have been observed between three RNA‐binding proteins and insulin resistance; therefore, increased type 2 diabetes risk. 35 , 36 Hence, the authors hypothesized an association between elevated RNA‐binding protein subunit (#38) levels and diabetic renal complications in T1DM patients with DN. 37 …”

“…RNA‐binding protein regulatory subunit 38, also known as Protein DJ‐1, is likely to be significantly more abundant in T1DM patients with DN due to specific mRNAs stabilization, a process by which cells may control protein expression levels 34 . Associations have been observed between three RNA‐binding proteins and insulin resistance; therefore, increased type 2 diabetes risk 35,36 . Hence, the authors hypothesized an association between elevated RNA‐binding protein subunit (#38) levels and diabetic renal complications in T1DM patients with DN 37 …”

Post-transcriptional control by RNA-binding proteins in diabetes and its related complications

“…In addition to endothelial cell dysfunction, diabetic vascular disease can further alter capillary density to affect coronary flow velocity reserve (CFVR), which in turn develops into coronary microvascular disease (CMD) ( Si et al, 2021 ). Previous research showed that HuR overexpression promotes angiogenesis via stabilizing VEGF-A mRNA and modifying endothelial cell angiogenic activity ( Chang et al, 2013 ).…”

“…In addition, diabetes attenuates the expression of Cx40, a gap junction channel protein, in cardiac ECs and impairs coronary microvascular function via downregulating the level of RNA-binding protein HuR. Overexpression of CX40 increased the density of capillary and ameliorated CFVR in diabetic mice ( Si et al, 2021 ).…”