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MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway

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-...

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Autores principales: Ding, Huaisheng, Yao, Jianhui, Xie, Hongxiang, Wang, Chengyu, Chen, Jing, Wei, Kaiyong, Ji, Yangyang, Liu, Lihong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514870/
https://www.ncbi.nlm.nih.gov/pubmed/34658906
http://dx.doi.org/10.3389/fphys.2021.709123
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author Ding, Huaisheng
Yao, Jianhui
Xie, Hongxiang
Wang, Chengyu
Chen, Jing
Wei, Kaiyong
Ji, Yangyang
Liu, Lihong
author_facet Ding, Huaisheng
Yao, Jianhui
Xie, Hongxiang
Wang, Chengyu
Chen, Jing
Wei, Kaiyong
Ji, Yangyang
Liu, Lihong
author_sort Ding, Huaisheng
collection PubMed
description 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.
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spelling pubmed-85148702021-10-15 MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway Ding, Huaisheng Yao, Jianhui Xie, Hongxiang Wang, Chengyu Chen, Jing Wei, Kaiyong Ji, Yangyang Liu, Lihong Front Physiol Physiology 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. Frontiers Media S.A. 2021-09-30 /pmc/articles/PMC8514870/ /pubmed/34658906 http://dx.doi.org/10.3389/fphys.2021.709123 Text en Copyright © 2021 Ding, Yao, Xie, Wang, Chen, Wei, Ji and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Ding, Huaisheng
Yao, Jianhui
Xie, Hongxiang
Wang, Chengyu
Chen, Jing
Wei, Kaiyong
Ji, Yangyang
Liu, Lihong
MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway
title MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway
title_full MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway
title_fullStr MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway
title_full_unstemmed MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway
title_short MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway
title_sort microrna-195-5p downregulation inhibits endothelial mesenchymal transition and myocardial fibrosis in diabetic cardiomyopathy by targeting smad7 and inhibiting transforming growth factor beta 1-smads-snail pathway
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514870/
https://www.ncbi.nlm.nih.gov/pubmed/34658906
http://dx.doi.org/10.3389/fphys.2021.709123
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