Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6.
Ischemia/reperfusion (I/R) affects the integrity of the endoplasmic reticulum (ER), the site of synthesis and folding of numerous proteins. Therefore, I/R may activate the unfolded protein response (UPR), resulting in the induction of a collection of ER stress proteins, many of which are protective and function to resolve the ER stress. In this study, we showed that when mouse hearts were subjected to ex vivo I/R, the levels of 2 ER stress-inducible markers of the UPR, the ER-targeted cytoprotective chaperones glucose-regulated proteins 78 and 94 (GRP78 and GRP94), were increased, consistent with I/R-mediated UPR activation in the heart. The UPR-mediated activation of ATF6 (Activation of Transcription Factor 6) induces cytoprotective ER stress proteins, including GRP78 and GRP94. To examine whether ATF6 protects the myocardium from I/R injury in the heart, we generated transgenic (TG) mice featuring cardiac-restricted expression of a novel tamoxifen-activated form of ATF6, ATF6-MER. When NTG and ATF6-MER TG mice were treated with or without tamoxifen for 5 days, only the hearts from the tamoxifen-treated TG mice exhibited increased levels of many ER stress-inducible mRNAs and proteins; for example, GRP78 and GRP94 transcript levels were increased by 8- and 15-fold, respectively. The tamoxifen-treated TG mouse hearts also exhibited better functional recovery from ex vivo I/R, as well as significantly reduced necrosis and apoptosis. These results suggest that the UPR is activated in the heart during I/R and that, as a result, the ATF6 branch of the UPR may induce expression of proteins that can function to reduce I/R injury.
Martindale
Joshua J
JJ
Heart Institute, Department of Biology, San Diego State University, San Diego, CA 92182, USA.
Fernandez
Rayne
R
Thuerauf
Donna
D
Whittaker
Ross
R
Gude
Natalie
N
Sussman
Mark A
MA
Glembotski
Christopher C
CC
D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D002478:Cells, Cultured; D004452:Echocardiography; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D015533:Transcriptional Activation
D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D002316:Cardiotonic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; C053387:endoplasmin; D013629:Tamoxifen