Selective enhancement of cardiomyocyte efficiency results in a pernicious heart condition

Abstract

Transgenic mice with selective induction of calreticulin transgene expression in cardiomyocytes (Cardiac CRT+) were analyzed. Cardiac CRT+ cardiomyocytes showed increased contractility and Ca 2+ transients. Yet, in vivo assessment of cardiac performance, and ischemic tolerance of Cardiac CRT+ mice demonstrated right ventricle dilation and reduced cardiac output, increased QT interval and decreased P amplitude. Paradoxically, ex vivo working hearts from Cardiac CRT+ mice showed enhanced ischemic cardio-protection and cardiac efficiency. Under aerobic conditions, Cardiac CRT+ hearts showed less efficient cardiac function than sham control hearts due to an increased ATP production from glycolysis relative to glucose oxidation. During reperfusion, this inefficiency was reversed, with Cardiac CRT+ hearts exhibiting better functional recovery and increased cardiac efficiency compared to sham control hearts. On the other hand, mechanical stretching of isolated cardiac fibroblasts activated the IRE1α branch of the unfolded protein response pathway as well as induction of Col1A2 and TGFβ gene expression ex vivo, which were all suppressed by tauroursodeoxycholic acid.

Inositol Requiring Enzyme (IRE), a multiplayer in sensing endoplasmic reticulum stress

“…Here we focus on selected aspects of the IRE1α structure, function, and regulation. Recent work also places IRE1α signaling as an important factor in physiology and pathology of the cardiovascular system (Groenendyk, Sreenivasaiah, Kim do, et al 2010 ; Groenendyk et al 2013 ; Glembotski 2014 ; Groenendyk et al 2016 ; Arrieta et al 2017 ; Groenendyk et al 2020 ).…”

Overexpression of Calreticulin Promotes Cardiac Fibroblasts Activation Via Regulating IRE1 Pathway

“…In our study, overexpression of CRT could promote the expression of α-SMA and the activation of CFs, which was consistent with the above results. The activation of CFs was involved in cardiac hypertrophy, dilated cardiomyopathy [25] and cardiac infarction [26], whose pathologic basis was myocardial remodeling. Moreover, recent study reported that CRT was the target gene of miR-455 and elevated expression of miR-455 can negatively regulate the CRT.…”

Calreticulin and the Heart

“…While increasing calreticulin abundance in adult cardiomyocytes improves ER/SR Ca 2+ capacity and delays store-operated Ca 2+ entry, it also stimulates the UPR, which promotes an increase in cardiac TGFβ abundance that, in turn, induces increased collagen deposition and severe cardiac fibrosis [ 33 , 34 ]. This is due to the mechanical stretching of cardiac fibroblasts because of enhanced cardiomyocyte efficiency and the activation of the IRE1α branch of the UPR pathway [ 36 ]. Interestingly, inhibition of IRE1α activation with tauroursodeoxycholic acid (TUDCA), a proteostasis promoter [ 37 ], prevents the development of cardiac fibrosis in hearts that are overexpressing calreticulin [ 34 , 38 ].…”