Abstract
In type 1 and type 2 diabetes mellitus, increased cardiac fibrosis, stiffness and associated diastolic dysfunction may be the earliest pathological phenomena in diabetic cardiomyopathy. Endothelial‐mesenchymal transition (EndMT) in endothelia cells (ECs) is a critical cellular phenomenon that increases cardiac fibroblasts (CFs) and cardiac fibrosis in diabetic hearts. The purpose of this paper is to explore the molecular mechanism of miR‐21 regulating EndMT and cardiac perivascular fibrosis in diabetic cardiomyopathy. In vivo, hyperglycaemia up‐regulated the mRNA level of miR‐21, aggravated cardiac dysfunction and collagen deposition. The condition was recovered by inhibition of miR‐21 following with improving cardiac function and decreasing collagen deposition. miR‐21 inhibition decreased cardiac perivascular fibrosis by suppressing EndMT and up‐regulating SMAD7 whereas activating p‐SMAD2 and p‐SMAD3. In vitro, high glucose (HG) up‐regulated miR‐21 and induced EndMT in ECs, which was decreased by inhibition of miR‐21. A highly conserved binding site of NF‐κB located in miR‐21 5′‐UTR was identified. In ECs, SMAD7 is directly regulated by miR‐21. In conclusion, the pathway of NF‐κB/miR‐21/SMAD7 regulated the process of EndMT in T1DM, in diabetic cardiomyopathy, which may be regarded as a potential clinical therapeutic target for cardiac perivascular fibrosis.
Highlights
Type 1 and type 2 diabetes mellitus (T1DM and T2DM) increased the risk of heart failure (HF),[1,2] thereby inducing cardiomyopathy, despite of the other cardiac risk factors, for instance, hypertension, atherosclerosis and valvular disease.[3,4,5]Cardiac fibrosis and early‐stage left ventricular (LV) hypertrophy are the characteristics of diabetic cardiomyopathy,[3,4] which often progresses to heart failure with reduced ejection fraction (HFrEF).[6]
Increasing evidence suggests that high glucose concentra‐ tion is associated with Endothelial‐mesenchymal transition (EndMT) in endothelia cells (ECs), the mechanism underlying the regulation of EndMT in T1DM is still unclear.[28]
We identified a highly conserved binding site of NF‐κB in miR‐21 5′‐ UTR and demonstrated that high glucose (HG) up‐regulated miR‐21 in Human umbilical vein endothelial cells (HUVECs) via up‐regulation of p65
Summary
Type 1 and type 2 diabetes mellitus (T1DM and T2DM) increased the risk of heart failure (HF),[1,2] thereby inducing cardiomyopathy (re‐ ferred to as diabetic cardiomyopathy), despite of the other cardiac risk factors, for instance, hypertension, atherosclerosis and valvular disease.[3,4,5]. Endothelial‐to‐mesenchymal transition (EndMT) in endothelia cells (ECs) is an important cellular phenomenon that increases CFs and cardiac fibrosis in diabetic hearts.[14,15,16] Fibroblast‐like cells, de‐ rived from ECs via EndMT, play a significant part in the pathogen‐ esis of cardiac fibrosis.[17,18] EndMT is characterized by decreased intercellular adhesion accompanied with alteration in cell polarity 19,20 wherein endothelial markers, for example, vascular endothelial cadherin (VE‐cadherin) and CD31 are significantly down‐regulated, while mesenchymal markers, for instance, fibroblast‐specific pro‐ tein‐1 (FSP‐1) and α‐smooth muscle actin (α‐SMA) are remarkably up‐regulated.[21] SMADs (R‐SMADs, Co‐SMADs and I‐SMADs), main signal transducers of TGF‐β superfamily receptors, compose a protein family with homologous structure.[22] SMAD2 and SMAD3 serve as R‐SMADs whereas SMAD7 belongs to I‐SMADs.[22] EndMT is induced by activated TGF‐β1/SMAD, MAPK/ERK and PI3K/Akt, in concert with p38 MAPK signalling pathway in ECs, thereby further promot‐ ing the cardiac fibrosis phenotype of diabetic cardiomyopathy.[23,24] In contrast, inhibition of these pathways can prevent TGF‐β‐induced cardiac fibrosis.[25] NF‐κB is a protein complex controls inflammation cytokine production and transcription of DNA, consisting of multiple members including RelA (p65) in mammalian cells.[26] P65, encoded by RELA gene,[27] is activated by fatty acids and hyperglycaemia in heart.[9] increasing evidence suggests that high glucose concentra‐ tion is associated with EndMT in ECs, the mechanism underlying the regulation of EndMT in T1DM is still unclear.[28]. The purpose of this research is to evaluate the role and the mode of miR‐21 in regulating EndMT and cardiac perivascular fibrosis and to ob‐ serve the influence of miR‐21 inhibition on the heart of diabetic cardiomyopathy
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