This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 99/3/275    most recent 01.RES.0000233317.70421.03v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thuerauf, D. J. Articles by Glembotski, C. C. Search for Related Content PubMed PubMed Citation Articles by Thuerauf, D. J. Articles by Glembotski, C. C. Related Collections Biochemistry and metabolism Apoptosis

(Circulation Research. 2006;99:275.)
© 2006 American Heart Association, Inc.

Cellular Biology

Activation of the Unfolded Protein Response in Infarcted Mouse Heart and Hypoxic Cultured Cardiac Myocytes

Donna J. Thuerauf, Marie Marcinko, Natalie Gude, Marta Rubio, Mark A. Sussman, Christopher C. Glembotski

From the San Diego State University Heart Institute and the Department of Biology, San Diego State University, Calif.

Correspondence to Christopher C. Glembotski, Director, SDSU Heart Institute and the Department of Biology, San Diego State University, San Diego, CA 92182. E-mail cglembotski{at}sciences.sdsu.edu

Endoplasmic reticulum (ER) stresses that reduce ER protein folding activate the unfolded protein response (UPR). One effector of the UPR is the transcription factor X-box binding protein-1 (XBP1), which is expressed on ER stress-mediated splicing of the XBP1 mRNA. XBP1 induces certain ER-targeted proteins, eg, glucose-regulated protein 78 (GRP78), that help resolve the ER stress and foster cell survival. In this study, we determined whether hypoxia can activate the UPR in the cardiac context. Neonatal rat ventricular myocyte cultures subjected to hypoxia (16 hours) exhibited increased XBP1 mRNA splicing, XBP1 protein expression, GRP78 promoter activation, and GRP78 protein levels; however, the levels of these UPR markers declined during reoxygenation, suggesting that the UPR is activated during hypoxia but not during reoxygenation. When cells were infected with a recombinant adenovirus (AdV) encoding dominant-negative XBP1 (AdV-XBP1dn), UPR markers were reduced; however, hypoxia/reoxygenation-induced apoptosis increased. Confocal immunocytofluorescence demonstrated that hypoxia induced GRP78 in neonatal rat and isolated adult mouse ventricular myocytes. Moreover, mouse hearts subjected to in vivo myocardial infarction exhibited increased GRP78 expression in cardiac myocytes near the infarct, but not in healthy cells distal to the infarct. These results indicate that hypoxia activates the UPR in cardiac myocytes and that XBP1-inducible proteins may contribute to protecting the myocardium during hypoxic stress.

Key Words: cardiac myocytes • cardiac transcription factors • chaperones • ER stress • hypoxia • ischemia • mouse • myocardial infarction • unfolded protein response

This article has been cited by other articles:

				M. Philippova, D. Ivanov, M. B. Joshi, E. Kyriakakis, K. Rupp, T. Afonyushkin, V. Bochkov, P. Erne, and T. J. Resink Identification of Proteins Associating with Glycosylphosphatidylinositol- Anchored T-Cadherin on the Surface of Vascular Endothelial Cells: Role for Grp78/BiP in T-Cadherin-Dependent Cell Survival Mol. Cell. Biol., June 15, 2008; 28(12): 4004 - 4017. [Abstract] [Full Text] [PDF]

				P. J. Belmont, A. Tadimalla, W. J. Chen, J. J. Martindale, D. J. Thuerauf, M. Marcinko, N. Gude, M. A. Sussman, and C. C. Glembotski Coordination of Growth and Endoplasmic Reticulum Stress Signaling by Regulator of Calcineurin 1 (RCAN1), a Novel ATF6-inducible Gene J. Biol. Chem., May 16, 2008; 283(20): 14012 - 14021. [Abstract] [Full Text] [PDF]

				K. Rantanen, J. Pursiheimo, H. Hogel, V. Himanen, E. Metzen, and P. M. Jaakkola Prolyl Hydroxylase PHD3 Activates Oxygen-dependent Protein Aggregation Mol. Biol. Cell, May 1, 2008; 19(5): 2231 - 2240. [Abstract] [Full Text] [PDF]

				J.-K. Jin, R. Whittaker, M. S. Glassy, S. B. Barlow, R. A. Gottlieb, and C. C. Glembotski Localization of phosphorylated {alpha}B-crystallin to heart mitochondria during ischemia-reperfusion Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H337 - H344. [Abstract] [Full Text] [PDF]

				C. C. Glembotski Endoplasmic Reticulum Stress in the Heart Circ. Res., November 9, 2007; 101(10): 975 - 984. [Abstract] [Full Text] [PDF]

				A. Severino, M. Campioni, S. Straino, F. N. Salloum, N. Schmidt, U. Herbrand, S. Frede, G. Toietta, G. Di Rocco, R. Bussani, et al. Identification of Protein Disulfide Isomerase as a Cardiomyocyte Survival Factor in Ischemic Cardiomyopathy J. Am. Coll. Cardiol., September 11, 2007; 50(11): 1029 - 1037. [Abstract] [Full Text] [PDF]

				D. J. Thuerauf, M. Marcinko, P. J. Belmont, and C. C. Glembotski Effects of the Isoform-specific Characteristics of ATF6{alpha} and ATF6beta on Endoplasmic Reticulum Stress Response Gene Expression and Cell Viability J. Biol. Chem., August 3, 2007; 282(31): 22865 - 22878. [Abstract] [Full Text] [PDF]

				J. Niu, A. Azfer, L. M. Rogers, X. Wang, and P. E. Kolattukudy Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy Cardiovasc Res, February 1, 2007; 73(3): 549 - 559. [Abstract] [Full Text] [PDF]