Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling
Abstract Myeloid differentiation protein 1 (MD1) has been implicated in numerous pathophysiological processes, including immune regulation, obesity, insulin resistance, and inflammation. However, the role of MD1 in cardiac remodelling remains incompletely understood. We used MD1-knockout (KO) mice a...
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2017-07-01
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doaj-78f4f0de2e7c4b4a84944dc3296482d32020-12-08T02:35:29ZengNature Publishing GroupScientific Reports2045-23222017-07-017111210.1038/s41598-017-05379-wLoss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodellingJianye Peng0Yu Liu1Xiaoju Xiong2Congxin Huang3Yang Mei4Zhiqiang Wang5Yanhong Tang6Jing Ye7Bin Kong8Wanli Liu9Teng Wang10He Huang11Department of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityDepartment of Cardiology, Renmin Hospital of Wuhan UniversityAbstract Myeloid differentiation protein 1 (MD1) has been implicated in numerous pathophysiological processes, including immune regulation, obesity, insulin resistance, and inflammation. However, the role of MD1 in cardiac remodelling remains incompletely understood. We used MD1-knockout (KO) mice and their wild-type littermates to determine the functional significance of MD1 in the regulation of aortic banding (AB)-induced left ventricular (LV) structural and electrical remodelling and its underlying mechanisms. After 4 weeks of AB, MD1-KO hearts showed substantial aggravation of LV hypertrophy, fibrosis, LV dilation and dysfunction, and electrical remodelling, which resulted in overt heart failure and increased electrophysiological instability. Moreover, MD1-KO-AB cardiomyocytes showed increased diastolic sarcoplasmic reticulum (SR) Ca2+ leak, reduced Ca2+ transient amplitude and SR Ca2+ content, decreased SR Ca2+-ATPase2 expression, and increased phospholamban and Na+/Ca2+-exchanger 1 protein expression. Mechanistically, the adverse effects of MD1 deletion on LV remodelling were related to hyperactivated CaMKII signalling and increased impairment of intracellular Ca2+ homeostasis, whereas the increased electrophysiological instability was partly attributed to exaggerated prolongation of cardiac repolarisation, decreased action potential duration alternans threshold, and increased diastolic SR Ca2+ leak. Therefore, our study on MD1 could provide new therapeutic strategies for preventing/treating heart failure.https://doi.org/10.1038/s41598-017-05379-w |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jianye Peng Yu Liu Xiaoju Xiong Congxin Huang Yang Mei Zhiqiang Wang Yanhong Tang Jing Ye Bin Kong Wanli Liu Teng Wang He Huang |
spellingShingle |
Jianye Peng Yu Liu Xiaoju Xiong Congxin Huang Yang Mei Zhiqiang Wang Yanhong Tang Jing Ye Bin Kong Wanli Liu Teng Wang He Huang Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling Scientific Reports |
author_facet |
Jianye Peng Yu Liu Xiaoju Xiong Congxin Huang Yang Mei Zhiqiang Wang Yanhong Tang Jing Ye Bin Kong Wanli Liu Teng Wang He Huang |
author_sort |
Jianye Peng |
title |
Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling |
title_short |
Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling |
title_full |
Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling |
title_fullStr |
Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling |
title_full_unstemmed |
Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling |
title_sort |
loss of md1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-07-01 |
description |
Abstract Myeloid differentiation protein 1 (MD1) has been implicated in numerous pathophysiological processes, including immune regulation, obesity, insulin resistance, and inflammation. However, the role of MD1 in cardiac remodelling remains incompletely understood. We used MD1-knockout (KO) mice and their wild-type littermates to determine the functional significance of MD1 in the regulation of aortic banding (AB)-induced left ventricular (LV) structural and electrical remodelling and its underlying mechanisms. After 4 weeks of AB, MD1-KO hearts showed substantial aggravation of LV hypertrophy, fibrosis, LV dilation and dysfunction, and electrical remodelling, which resulted in overt heart failure and increased electrophysiological instability. Moreover, MD1-KO-AB cardiomyocytes showed increased diastolic sarcoplasmic reticulum (SR) Ca2+ leak, reduced Ca2+ transient amplitude and SR Ca2+ content, decreased SR Ca2+-ATPase2 expression, and increased phospholamban and Na+/Ca2+-exchanger 1 protein expression. Mechanistically, the adverse effects of MD1 deletion on LV remodelling were related to hyperactivated CaMKII signalling and increased impairment of intracellular Ca2+ homeostasis, whereas the increased electrophysiological instability was partly attributed to exaggerated prolongation of cardiac repolarisation, decreased action potential duration alternans threshold, and increased diastolic SR Ca2+ leak. Therefore, our study on MD1 could provide new therapeutic strategies for preventing/treating heart failure. |
url |
https://doi.org/10.1038/s41598-017-05379-w |
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