Abstract
Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus, which is associated with fibrosis and microRNAs (miRs). This study estimated the mechanism of miR-195-5p in endothelial mesenchymal transition (EndMT) and myocardial fibrosis in DCM. After the establishment of DCM rat models, miR-195-5p was silenced by miR-195-5p antagomir. The cardiac function-related indexes diastolic left ventricular anterior wall (LVAW, d), systolic LVAW (d), diastolic left ventricular posterior wall (LVPW, d), systolic LVPW (d), left ventricular ejection fraction (LVEF), and fractional shortening (FS) were measured and miR-195-5p expression in myocardial tissue was detected. Myocardial fibrosis, collagen deposition, and levels of fibrosis markers were detected. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose (HG) and miR-195-5p was silenced. The levels of fibrosis proteins, endothelial markers, fibrosis markers, EndMT markers, and transforming growth factor beta 1 (TGF-β1)/Smads pathway-related proteins were measured in HUVECs. The interaction between miR-195-5p and Smad7 was verified. In vivo, miR-195-5p was highly expressed in the myocardium of DCM rats. Diastolic and systolic LVAW, diastolic and systolic LVPW were increased and LVEF and FS were decreased. Inhibition of miR-195-5p reduced cardiac dysfunction, myocardial fibrosis, collagen deposition, and EndMT, promoted CD31 and VE-cadehrin expressions, and inhibited α-SMA and vimentin expressions. In vitro, HG-induced high expression of miR-195-5p and the expression changes of endothelial markers CD31, VE-cadehrin and fibrosis markers α-SMA and vimentin were consistent with those in vivo after silencing miR-195-5p. In mechanism, miR-195-5p downregulation blocked EndMT by inhibiting TGF-β1-smads pathway. Smad7 was the direct target of miR-195-5p and silencing miR-195-5p inhibited EndMT by promoting Smad7 expression. Collectively, silencing miR-195-5p inhibits TGF-β1-smads-snail pathway by targeting Smad7, thus inhibiting EndMT and alleviating myocardial fibrosis in DCM.
Highlights
Diabetes is characterized by dynamic changes in blood glucose levels, which are associated with multiple complications, especially cardiomyopathy and endothelial dysfunction (Zhang and Sun, 2020)
Endothelial mesenchymal transition is the result of high glucose (HG)-induced endothelial damage, which is related to the pathology of myocardial fibrosis in Diabetic cardiomyopathy (DCM) (Zheng et al, 2019; Li et al, 2020)
MiR-195-5p expression in DCM rats and HG-induced Endothelial cells (ECs) was significantly increased in the present study
Summary
Diabetes is characterized by dynamic changes in blood glucose levels, which are associated with multiple complications, especially cardiomyopathy and endothelial dysfunction (Zhang and Sun, 2020). DCM is mainly characterized by diastolic dysfunction, left ventricular hypertrophy, cardiac stiffness, and myocardial fibrosis in the absence of hypertension or coronary artery disease (Lourenco et al, 2018; Haye et al, 2020). Endothelial cells (ECs) are quiescent under healthy conditions and important to maintain vascular homeostasis and endothelial dysfunction may be the primary mechanism involved in the pathogenesis of DCM (Knapp et al, 2019). EndMT contributes significantly to myocardial fibrosis, and prevention of EndMT may be a promising therapeutic strategy for DCM (Medici et al, 2011; Zhu et al, 2018; Wang et al, 2020a). The mechanisms of EndMT are not fully understood and no treatment to prevent or reverse the underlying molecular changes exists at this time
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