Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6 - PubMed (original) (raw)

Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6

Joshua J Martindale et al. Circ Res. 2006.

Abstract

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.

PubMed Disclaimer

Comment in

Viewing a stressful episode of ER: is ATF6 the triage nurse?
Benjamin IJ. Benjamin IJ. Circ Res. 2006 May 12;98(9):1120-2. doi: 10.1161/01.RES.0000223522.47948.16. Circ Res. 2006. PMID: 16690892 Review. No abstract available.

Cited by

Endoplasmic reticulum stress in diseases.
Liu Y, Xu C, Gu R, Han R, Li Z, Xu X. Liu Y, et al. MedComm (2020). 2024 Aug 26;5(9):e701. doi: 10.1002/mco2.701. eCollection 2024 Sep. MedComm (2020). 2024. PMID: 39188936 Free PMC article. Review.
Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress.
Barr LA, Shimizu Y, Lambert JP, Nicholson CK, Calvert JW. Barr LA, et al. Nitric Oxide. 2015 Apr 30;46:145-56. doi: 10.1016/j.niox.2014.12.013. Epub 2015 Jan 6. Nitric Oxide. 2015. PMID: 25575644 Free PMC article.
Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response.
Belmont PJ, Chen WJ, Thuerauf DJ, Glembotski CC. Belmont PJ, et al. J Mol Cell Cardiol. 2012 May;52(5):1176-82. doi: 10.1016/j.yjmcc.2012.01.017. Epub 2012 Feb 1. J Mol Cell Cardiol. 2012. PMID: 22326432 Free PMC article.
Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury.
Hu C, Tian Y, Xu H, Pan B, Terpstra EM, Wu P, Wang H, Li F, Liu J, Wang X. Hu C, et al. J Clin Invest. 2018 Dec 3;128(12):5294-5306. doi: 10.1172/JCI98287. Epub 2018 Oct 22. J Clin Invest. 2018. PMID: 30204128 Free PMC article.
Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy.
Niu J, Azfer A, Rogers LM, Wang X, Kolattukudy PE. Niu J, et al. Cardiovasc Res. 2007 Feb 1;73(3):549-59. doi: 10.1016/j.cardiores.2006.11.031. Epub 2006 Nov 30. Cardiovasc Res. 2007. PMID: 17207782 Free PMC article.

Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6 - PubMed (original) (raw)