Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression

Journal article


He, Jinli, Gong, Mengqi, Wang, Zaojia, Liu, Daiqi, Xie, Bingxin, Luo, C., Li, Guangping, Tse, Gary and Liu, T. 2021. Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression. Clinical and Experimental Pharmacology and Physiology. https://doi.org/10.1111/1440-1681.13541
AuthorsHe, Jinli, Gong, Mengqi, Wang, Zaojia, Liu, Daiqi, Xie, Bingxin, Luo, C., Li, Guangping, Tse, Gary and Liu, T.
Abstract

The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenic factor in cardiovascular diseases. The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. A total of 30 rats were randomly divided into control, ER stress inducer (tunicamycin[TN]) and ER stress inhibitor (tunicamycin+4-phenylbutyric acid [4-PBA]) groups. ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), left ventricular peaksystolic pressure(LVSP) and LV end-diastolic pressure(LVEDP). Epicardial mapping performed in vivo revealed reduced conduction velocity and increased conduction heterogeneity associated with the development of spontaneous ventricular tachycardia. Masson’s trichrome staining revealed marked fibrosis in the myocardial interstitial and sub-pericardial regions, and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor transforming growth factor-β1 (TGF-β1), decreased mitochondrial biogenesis protein peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC-1a), and decreased mitochondrial fusion protein mitofusin-2 (MFN2). These changes were associated with mitochondria dysfunction and connexin 43(CX43)translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodelling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA.

KeywordsPhysiology (medical); Physiology; Pharmacology
Year2021
JournalClinical and Experimental Pharmacology and Physiology
PublisherWiley
ISSN0305-1870
1440-1681
Digital Object Identifier (DOI)https://doi.org/10.1111/1440-1681.13541
Official URLhttps://onlinelibrary.wiley.com/doi/abs/10.1111/1440-1681.13541
FunderNatural Science Foundation of Tianjin City
National Natural Science Foundation of China
Publication dates
Online06 Jul 2021
Publication process dates
Deposited12 Jul 2021
Accepted10 Jun 2021
Accepted author manuscript
Output statusPublished
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