Groenendyk Jody, Wang Qian, Wagg Cory, Lee Dukgyu, Robinson Alison, Barr Amy, Light Peter E, Lopaschuk Gary D, Agellon Luis B, Michalak Marek
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
PLoS One. 2020 Aug 13;15(8):e0236457. doi: 10.1371/journal.pone.0236457. eCollection 2020.
Transgenic mice with selective induction of calreticulin transgene expression in cardiomyocytes (CardiacCRT+) were analyzed. CardiacCRT+ cardiomyocytes showed increased contractility and Ca2+ transients. Yet, in vivo assessment of cardiac performance, and ischemic tolerance of CardiacCRT+ mice demonstrated right ventricle dilation and reduced cardiac output, increased QT interval and decreased P amplitude. Paradoxically, ex vivo working hearts from CardiacCRT+ mice showed enhanced ischemic cardio-protection and cardiac efficiency. Under aerobic conditions, CardiacCRT+ 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 CardiacCRT+ 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.
对在心肌细胞中选择性诱导钙网蛋白转基因表达的转基因小鼠（心脏CRT+）进行了分析。心脏CRT+心肌细胞显示收缩性增加和Ca2+瞬变增加。然而，对心脏CRT+小鼠的心脏功能和缺血耐受性进行的体内评估显示右心室扩张、心输出量减少、QT间期延长和P波振幅降低。矛盾的是，来自心脏CRT+小鼠的离体工作心脏显示出增强的缺血心脏保护作用和心脏效率。在有氧条件下，由于相对于葡萄糖氧化，糖酵解产生的ATP增加，心脏CRT+心脏的心脏功能比假手术对照心脏效率更低。在再灌注期间，这种低效率被逆转，与假手术对照心脏相比，心脏CRT+心脏表现出更好的功能恢复和更高的心脏效率。另一方面，离体心脏成纤维细胞的机械拉伸激活了未折叠蛋白反应途径的IRE1α分支以及Col1A2和TGFβ基因表达的诱导，而这些都被牛磺熊去氧胆酸抑制。
