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

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.

Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

“…Therefore, in zebrafish, the data confirmed that S1R activity is not a requisite to mitochondria physiology but appears necessary, as S1R invalidation resulted in a −26% decrease in basal respiration and −34% in the respiration related to the formation of ATP. Induction of ER stress by Tunicamycin resulted in significant alterations of the different parameters related to oxidative respiration, as previously observed [46,73,74] that were progressive and observed at shorter exposure times (2 h, 4 h, data not shown). Interestingly, loss of S1R abolished the decrease of basal and ATP-linked OCR after Tunicamycin treatment, suggesting that S1R was necessary for the adaptation of mitochondrial physiology to ER stress.…”

Connexin 43 in Mitochondria: What Do We Really Know About Its Function?

“…Furthermore, Cx43 is detected within mitochondria isolated from stem cell antigen-1 + ( Lu et al, 2010 ) and H9c2 cells ( Tu et al, 2017 ; Pecoraro et al, 2021 ), from brown adipose tissue ( Kim et al, 2017 ), from astrocytes ( Kozoriz et al, 2010 ) and brain ( Azarashvili et al, 2011 ) as well as from liver ( Li et al, 2021 ). Most studies, however, focused on the mitochondrial localization of Cx43 in the heart ( Boengler et al, 2005 ; Gorbe et al, 2011 ; Srisakuldee et al, 2014 ; Shan et al, 2015 ; Gadicherla et al, 2017 ; Wang et al, 2019 ; He et al, 2021 ; Wei et al, 2022 ) including neonatal cardiomyocytes ( Tu et al, 2017 ) and embryonic stem cell-derived cardiomyocytes ( Wang et al, 2021 ). Mitochondria from mice with inducible Cx43 knockout ( Boengler et al, 2005 ; Gadicherla et al, 2017 ; Wang et al, 2019 ) or mice in which Cx43 was replaced by Cx32 ( Miro-Casas et al, 2009 ) served as respective negative controls.…”

Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin‐induced myocardial injury

“…Mitochondrial quality control is mediated by a homeostatic balance between mitochondrial biogenesis and degradation, mainly regulated by dynamic processes such as mitochondrial fission and fusion, mitochondrial cristae remodeling, mitochondrial biosynthesis, Ca 2+ homeostasis, and mitophagy [ 15 ]. In various animal models, mitochondrial damage produces a large number of oxidative substances that lead to myocardial apoptosis, ultimately leading to remodeling of the atria [ 16 , 17 , 18 , 19 , 20 ] and/or ventricles [ 18 , 21 , 22 ], and decreased cardiac function. MFN2 is a mitochondrial fusion protein mainly involved in the fusion of mitochondria.…”