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Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart

Diabetes mellitus is often associated with cardiovascular complications, which is the leading cause of morbidity and mortality among patients with diabetes mellitus, but little is known about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. OBJECTIVE: W...

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Autores principales: Li, Huaping, Fan, Jiahui, Zhao, Yanru, Zhang, Xiaorong, Dai, Beibei, Zhan, Jiabing, Yin, Zhongwei, Nie, Xiang, Fu, Xiang-Dong, Chen, Chen, Wang, Dao Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903355/
https://www.ncbi.nlm.nih.gov/pubmed/31638474
http://dx.doi.org/10.1161/CIRCRESAHA.119.314898
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author Li, Huaping
Fan, Jiahui
Zhao, Yanru
Zhang, Xiaorong
Dai, Beibei
Zhan, Jiabing
Yin, Zhongwei
Nie, Xiang
Fu, Xiang-Dong
Chen, Chen
Wang, Dao Wen
author_facet Li, Huaping
Fan, Jiahui
Zhao, Yanru
Zhang, Xiaorong
Dai, Beibei
Zhan, Jiabing
Yin, Zhongwei
Nie, Xiang
Fu, Xiang-Dong
Chen, Chen
Wang, Dao Wen
author_sort Li, Huaping
collection PubMed
description Diabetes mellitus is often associated with cardiovascular complications, which is the leading cause of morbidity and mortality among patients with diabetes mellitus, but little is known about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. OBJECTIVE: We aim to elucidate the mechanism underlying hyperglycemia-induced cardiac dysfunction on a well-established db/db mouse model for diabetes mellitus and diabetic complications that lead to heart failure. METHODS AND RESULTS: We first profiled the expression of microRNAs (miRNAs) by microarray and quantitative reverse transcription polymerase chain reaction on db/db mice and identified miR-320 as a key miRNA associated with the disease phenotype. We next established the clinical relevance of this finding by showing the upregulation of the same miRNA in the failing heart of patients with diabetes mellitus. We demonstrated the causal role of miR-320 in inducing diabetic cardiomyopathy, showing that miR-320 overexpression exacerbated while its inhibition improved the cardiac phenotype in db/db mice. Unexpectedly, we found that miR-320 acts as a small activating RNA in the nucleus at the level of transcription. By chromatin immunoprecipitation sequencing and chromatin immunoprecipitation quantitive polymerase chain reaction analysis of Ago2 (argonaute RISC catalytic component 2) and RNA polymerase II in response to miR-320 induction, we identified CD36 (fatty acid translocase) as a key target gene for this miRNA and showed that the induced expression of CD36 is responsible for increased fatty acid uptake, thereby causing lipotoxicity in the heart. CONCLUSIONS: These findings uncover a novel mechanism for diabetes mellitus–triggered cardiac dysfunction, provide an endogenous case for small activating RNA that has been demonstrated to date only with synthetic RNAs in transfected cells, and suggest a potential strategy to develop a miRNA-based therapy to treat diabetes mellitus–associated cardiovascular complications.
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spelling pubmed-69033552020-01-22 Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart Li, Huaping Fan, Jiahui Zhao, Yanru Zhang, Xiaorong Dai, Beibei Zhan, Jiabing Yin, Zhongwei Nie, Xiang Fu, Xiang-Dong Chen, Chen Wang, Dao Wen Circ Res Original Research Diabetes mellitus is often associated with cardiovascular complications, which is the leading cause of morbidity and mortality among patients with diabetes mellitus, but little is known about the mechanism that connects diabetes mellitus to the development of cardiovascular dysfunction. OBJECTIVE: We aim to elucidate the mechanism underlying hyperglycemia-induced cardiac dysfunction on a well-established db/db mouse model for diabetes mellitus and diabetic complications that lead to heart failure. METHODS AND RESULTS: We first profiled the expression of microRNAs (miRNAs) by microarray and quantitative reverse transcription polymerase chain reaction on db/db mice and identified miR-320 as a key miRNA associated with the disease phenotype. We next established the clinical relevance of this finding by showing the upregulation of the same miRNA in the failing heart of patients with diabetes mellitus. We demonstrated the causal role of miR-320 in inducing diabetic cardiomyopathy, showing that miR-320 overexpression exacerbated while its inhibition improved the cardiac phenotype in db/db mice. Unexpectedly, we found that miR-320 acts as a small activating RNA in the nucleus at the level of transcription. By chromatin immunoprecipitation sequencing and chromatin immunoprecipitation quantitive polymerase chain reaction analysis of Ago2 (argonaute RISC catalytic component 2) and RNA polymerase II in response to miR-320 induction, we identified CD36 (fatty acid translocase) as a key target gene for this miRNA and showed that the induced expression of CD36 is responsible for increased fatty acid uptake, thereby causing lipotoxicity in the heart. CONCLUSIONS: These findings uncover a novel mechanism for diabetes mellitus–triggered cardiac dysfunction, provide an endogenous case for small activating RNA that has been demonstrated to date only with synthetic RNAs in transfected cells, and suggest a potential strategy to develop a miRNA-based therapy to treat diabetes mellitus–associated cardiovascular complications. Lippincott Williams & Wilkins 2019-12-06 2019-10-22 /pmc/articles/PMC6903355/ /pubmed/31638474 http://dx.doi.org/10.1161/CIRCRESAHA.119.314898 Text en © 2019 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
spellingShingle Original Research
Li, Huaping
Fan, Jiahui
Zhao, Yanru
Zhang, Xiaorong
Dai, Beibei
Zhan, Jiabing
Yin, Zhongwei
Nie, Xiang
Fu, Xiang-Dong
Chen, Chen
Wang, Dao Wen
Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
title Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
title_full Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
title_fullStr Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
title_full_unstemmed Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
title_short Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart
title_sort nuclear mir-320 mediates diabetes-induced cardiac dysfunction by activating transcription of fatty acid metabolic genes to cause lipotoxicity in the heart
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903355/
https://www.ncbi.nlm.nih.gov/pubmed/31638474
http://dx.doi.org/10.1161/CIRCRESAHA.119.314898
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