The Role of the Unfolded Protein Response in the Heart

Overview

Journal J Mol Cell Cardiol

Specialty Cardiology & Vascular Diseases

Date 2007 Dec 7

PMID 18054039

Citations 70

Authors

Christopher C Glembotski

Affiliations

Soon will be listed here.

Abstract

The misfolding of nascent proteins, or the unfolding of proteins after synthesis is complete, can occur in response to numerous environmental stresses, or as a result of mutations that de-stabilize protein structure. Cells have developed elaborate protein quality control systems that recognize improperly folded proteins and either refold them or facilitate their degradation. One such quality control system is the unfolded protein response, or the UPR. The UPR is a highly conserved signal transduction system that is activated when cells are subjected to conditions that alter the endoplasmic reticulum (ER) in ways that impair the folding of nascent proteins in this organelle. Recent observations indicate that in the heart, the UPR is activated during acute stresses, including ischemia/reperfusion, as well as upon longer term stresses that lead to cardiac hypertrophy and heart failure. Moreover, certain aspects of the UPR are activated during, and are required for proper heart development. This review summarizes recent studies of the UPR in the heart, focusing on the possible roles of the UPR in contributing to, or protecting from ischemia/reperfusion damage.

Citing Articles

One day of environment-induced heat stress damages the murine myocardium.

Roths M, Rudolph T, Krishna S, Michael A, Selsby J Am J Physiol Heart Circ Physiol. 2024; 327(4):H978-H988.

PMID: 39212770 PMC: 11482254. DOI: 10.1152/ajpheart.00180.2024.

Cardiovascular protection of YiyiFuzi powder and the potential mechanisms through modulating mitochondria-endoplasmic reticulum interactions.

Ding J, Ji R, Wang Z, Jia Y, Meng T, Song X Front Pharmacol. 2024; 15:1405545.

PMID: 38978978 PMC: 11228702. DOI: 10.3389/fphar.2024.1405545.

The total xanthones extracted from Gentianella acuta alleviates HFpEF by activating the IRE1α/Xbp1s pathway.

Zhao L, Qin Y, Liu Y, An L, Liu W, Zhang C J Cell Mol Med. 2024; 28(11):e18466.

PMID: 38847482 PMC: 11157675. DOI: 10.1111/jcmm.18466.

Lipotoxicity, ER Stress, and Cardiovascular Disease: Current Understanding and Future Directions.

Shreya S, Alam M, Anupriya , Jaiswal S, Rani V, Jain B Cardiovasc Hematol Agents Med Chem. 2023; 22(3):319-335.

PMID: 37859305 DOI: 10.2174/0118715257262366230928051902.

Editorial: The role of calcium and calcium binding proteins in cell physiology and disease.

Thomas N, Dart C, Helassa N Front Physiol. 2023; 14:1228885.

PMID: 37362430 PMC: 10289193. DOI: 10.3389/fphys.2023.1228885.

References

Shi Y, Vattem K, Sood R, An J, Liang J, Stramm L . Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 1998; 18(12):7499-509. PMC: 109330. DOI: 10.1128/MCB.18.12.7499. View

Shamu C, Cox J, Walter P . The unfolded-protein-response pathway in yeast. Trends Cell Biol. 1994; 4(2):56-60. DOI: 10.1016/0962-8924(94)90011-6. View

Kozutsumi Y, Segal M, Normington K, Gething M, Sambrook J . The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature. 1988; 332(6163):462-4. DOI: 10.1038/332462a0. View

Ma K, Vattem K, Wek R . Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J Biol Chem. 2002; 277(21):18728-35. DOI: 10.1074/jbc.M200903200. View

Paschen W . Endoplasmic reticulum dysfunction in brain pathology: critical role of protein synthesis. Curr Neurovasc Res. 2005; 1(2):173-81. DOI: 10.2174/1567202043480125. View

Toth A, Jeffers J, Nickson P, Min J, Morgan J, Zambetti G . Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2006; 291(1):H52-60. DOI: 10.1152/ajpheart.01046.2005. View

Shamu C, Walter P . Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 1996; 15(12):3028-39. PMC: 450244. View

Calfon M, Zeng H, Urano F, Till J, Hubbard S, Harding H . IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002; 415(6867):92-6. DOI: 10.1038/415092a. View

MCMILLAN D, Gething M, Sambrook J . The cellular response to unfolded proteins: intercompartmental signaling. Curr Opin Biotechnol. 1994; 5(5):540-5. DOI: 10.1016/0958-1669(94)90071-x. View

10.

Kondo S, Murakami T, Tatsumi K, Ogata M, Kanemoto S, Otori K . OASIS, a CREB/ATF-family member, modulates UPR signalling in astrocytes. Nat Cell Biol. 2005; 7(2):186-94. DOI: 10.1038/ncb1213. View

11.

Azfer A, Niu J, Rogers L, Adamski F, Kolattukudy P . Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. Am J Physiol Heart Circ Physiol. 2006; 291(3):H1411-20. PMC: 1575464. DOI: 10.1152/ajpheart.01378.2005. View

12.

Qi X, Vallentin A, Churchill E, Mochly-Rosen D . deltaPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart. J Mol Cell Cardiol. 2007; 43(4):420-8. PMC: 2185772. DOI: 10.1016/j.yjmcc.2007.07.061. View

13.

Meusser B, Hirsch C, Jarosch E, Sommer T . ERAD: the long road to destruction. Nat Cell Biol. 2005; 7(8):766-72. DOI: 10.1038/ncb0805-766. View

14.

Martindale J, Fernandez R, Thuerauf D, Whittaker R, Gude N, Sussman M . Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circ Res. 2006; 98(9):1186-93. DOI: 10.1161/01.RES.0000220643.65941.8d. View

15.

Barnes J, Smoak I . Glucose-regulated protein 78 (GRP78) is elevated in embryonic mouse heart and induced following hypoglycemic stress. Anat Embryol (Berl). 2000; 202(1):67-74. DOI: 10.1007/s004290000090. View

16.

Cox J, Shamu C, Walter P . Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell. 1993; 73(6):1197-206. DOI: 10.1016/0092-8674(93)90648-a. View

17.

Thuerauf D, Marcinko M, Gude N, Rubio M, Sussman M, Glembotski C . Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circ Res. 2006; 99(3):275-82. DOI: 10.1161/01.RES.0000233317.70421.03. View

18.

Takagi H, Matsui Y, Sadoshima J . The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the heart. Antioxid Redox Signal. 2007; 9(9):1373-81. DOI: 10.1089/ars.2007.1689. View

19.

Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding H . Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000; 287(5453):664-6. DOI: 10.1126/science.287.5453.664. View

20.

Brodsky J . The protective and destructive roles played by molecular chaperones during ERAD (endoplasmic-reticulum-associated degradation). Biochem J. 2007; 404(3):353-63. PMC: 2747773. DOI: 10.1042/BJ20061890. View