Skip to main content
SpringerLink
Log in

The role of the ER stress sensor IRE1 in cardiovascular diseases

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Despite enormous advances in the treatment of cardiovascular diseases, including I/R injury and heart failure, heart diseases remain a leading cause of mortality worldwide. Inositol-requiring enzyme 1 (IRE1) is an evolutionarily conserved sensor endoplasmic reticulum (ER) transmembrane protein that senses ER stress. It manages ER stress induced by the accumulation of unfolded/misfolded proteins via the unfolded protein response (UPR). However, if the stress still persists, the UPR pathways are activated and induce cell death. Emerging evidence shows that, beyond the UPR, IRE1 participates in the progression of cardiovascular diseases by regulating inflammation levels, immunity, and lipid metabolism. Here, we summarize the recent findings and discuss the potential therapeutic effects of IRE1 in the treatment of cardiovascular diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Enquiries about data availability should be directed to the authors.

References

  1. Ren J, Bi Y, Sowers JR, Hetz C, Zhang Y (2021) Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat Rev Cardiol 18:499–521. https://doi.org/10.1038/s41569-021-00511-w

    Article  PubMed  Google Scholar 

  2. Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, Pytel D, Diehl JA, Majsterek I (2021) The structure, activation and signaling of ire1 and its role in determining cell fate. Biomedicines. https://doi.org/10.3390/biomedicines9020156

    Article  PubMed  PubMed Central  Google Scholar 

  3. Junjappa RP, Patil P, Bhattarai KR, Kim HR, Chae HJ (2018) IRE1α implications in endoplasmic reticulum stress-mediated development and pathogenesis of autoimmune diseases. Front Immunol 9:1289. https://doi.org/10.3389/fimmu.2018.01289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zheng Z, Shang Y, Tao J, Zhang J, Sha B (2019) Endoplasmic reticulum stress signaling pathways: activation and diseases. Curr Protein Pept Sci 20:935–943. https://doi.org/10.2174/1389203720666190621103145

    Article  CAS  PubMed  Google Scholar 

  5. Wang M, Kaufman RJ (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529:326–335. https://doi.org/10.1038/nature17041

    Article  CAS  PubMed  Google Scholar 

  6. Hetz C, Zhang K, Kaufman RJ (2020) Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol 21:421–438. https://doi.org/10.1038/s41580-020-0250-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H, Leonardi R, Chen YE, Jackowski S, Kaufman RJ (2011) The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. Embo j 30:1357–1375. https://doi.org/10.1038/emboj.2011.52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Karagöz GE, Acosta-Alvear D, Nguyen HT, Lee CP, Chu F, Walter P (2017) An unfolded protein-induced conformational switch activates mammalian IRE1. Elife. https://doi.org/10.7554/eLife.30700

    Article  PubMed  PubMed Central  Google Scholar 

  9. Waldherr SM, Strovas TJ, Vadset TA, Liachko NF, Kraemer BC (2019) Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau. Nat Commun 10:4443. https://doi.org/10.1038/s41467-019-12070-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. He Y, Beatty A, Han X, Ji Y, Ma X, Adelstein RS, Yates JR 3rd, Kemphues K, Qi L (2012) Nonmuscle myosin IIB links cytoskeleton to IRE1α signaling during ER stress. Dev Cell 23:1141–1152. https://doi.org/10.1016/j.devcel.2012.11.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fernández D, Geisse A, Bernales JI, Lira A, Osorio F (2021) The unfolded protein response in immune cells as an emerging regulator of neuroinflammation. Front Aging Neurosci 13:682633. https://doi.org/10.3389/fnagi.2021.682633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Woodward AM, Di Zazzo A, Bonini S, Argüeso P (2020) Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface. Sci Rep 10:2216. https://doi.org/10.1038/s41598-020-59237-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, Greene S, Zeng Q, Fazli L, Rennie PS, Mills IG, Danielsen H, Theis F, Patterson JB, Jin Y, Saatcioglu F (2019) IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat Commun 10:323. https://doi.org/10.1038/s41467-018-08152-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Grandjean JMD, Madhavan A, Cech L, Seguinot BO, Paxman RJ, Smith E, Scampavia L, Powers ET, Cooley CB, Plate L, Spicer TP, Kelly JW, Wiseman RL (2020) Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming. Nat Chem Biol 16:1052–1061. https://doi.org/10.1038/s41589-020-0584-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Song M, Sandoval TA, Chae CS, Chopra S, Tan C, Rutkowski MR, Raundhal M, Chaurio RA, Payne KK, Konrad C, Bettigole SE, Shin HR, Crowley MJP, Cerliani JP, Kossenkov AV, Motorykin I, Zhang S, Manfredi G, Zamarin D, Holcomb K, Rodriguez PC, Rabinovich GA, Conejo-Garcia JR, Glimcher LH, Cubillos-Ruiz JR (2018) IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562:423–428. https://doi.org/10.1038/s41586-018-0597-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Qiu LZ, Yue LX, Ni YH, Zhou W, Huang CS, Deng HF, Wang NN, Liu H, Liu X, Zhou YQ, Xiao CR, Wang YG, Gao Y (2021) Emodin-Induced oxidative inhibition of mitochondrial function assists BiP/IRE1α/CHOP signaling-mediated ER-related apoptosis. Oxid Med Cell Longev 2021:8865813. https://doi.org/10.1155/2021/8865813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xie X, Ma X, Zeng S, Tang W, Xiao L, Zhu C, Yu R (2020) Mechanisms of berberine for the treatment of atherosclerosis based on network pharmacology. Evid Based Complement Alternat Med 2020:3568756. https://doi.org/10.1155/2020/3568756

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gimbrone MA Jr, García-Cardeña G (2016) Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 118:620–636. https://doi.org/10.1161/circresaha.115.306301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Poznyak A, Grechko AV, Poggio P, Myasoedova VA, Alfieri V, Orekhov AN (2020) The diabetes mellitus-atherosclerosis connection: the role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci. https://doi.org/10.3390/ijms21051835

    Article  PubMed  PubMed Central  Google Scholar 

  20. Shao BZ, Han BZ, Zeng YX, Su DF, Liu C (2016) The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol Sin 37:150–156. https://doi.org/10.1038/aps.2015.87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fu F, Doroudgar S (2022) IRE1/XBP1 and endoplasmic reticulum signaling - from basic to translational research for cardiovascular disease. Curr Opin Physiol 28:100552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Roy P, Orecchioni M, Ley K (2022) How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol 22:251–265. https://doi.org/10.1038/s41577-021-00584-1

    Article  CAS  PubMed  Google Scholar 

  23. Tufanli O, Telkoparan Akillilar P, Acosta-Alvear D, Kocaturk B, Onat UI, Hamid SM, Çimen I, Walter P, Weber C, Erbay E (2017) Targeting IRE1 with small molecules counteracts progression of atherosclerosis. Proc Natl Acad Sci 114:E1395-e1404. https://doi.org/10.1073/pnas.1621188114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Obacz J, Archambeau J, Lafont E, Nivet M, Martin S, Aubry M, Voutetakis K, Pineau R, Boniface R, Sicari D, Pelizzari-Raymundo D, Ghukasyan G, McGrath E, Vlachavas EI, Le Gallo M, Le Reste PJ, Barroso K, Fainsod-Levi T, Obiedat A, Granot Z, Tirosh B, Samal J, Pandit A, Negroni L, Soriano N, Monnier A, Mosser J, Chatziioannou A, Quillien V, Chevet E, Avril T (2023) IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma. Neuro Oncol. https://doi.org/10.1093/neuonc/noad256

    Article  Google Scholar 

  25. Yildirim Z, Baboo S, Hamid SM, Dogan AE, Tufanli O, Robichaud S, Emerton C, Diedrich JK, Vatandaslar H, Nikolos F, Gu Y, Iwawaki T, Tarling E, Ouimet M, Nelson DL, Yates JR 3rd, Walter P, Erbay E (2022) Intercepting IRE1 kinase-FMRP signaling prevents atherosclerosis progression. EMBO Mol Med 14:e15344. https://doi.org/10.15252/emmm.202115344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ketelhuth DFJ, Lutgens E, Back M, Binder CJ, Van den Bossche J, Daniel C, Dumitriu IE, Hoefer I, Libby P, O’Neill L, Weber C, Evans PC (2019) Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the working group on atherosclerosis and vascular biology of the European society of cardiology. Cardiovasc Res 115:1385–1392. https://doi.org/10.1093/cvr/cvz166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yao S, Yang N, Song G, Sang H, Tian H, Miao C, Zhang Y, Qin S (2012) Minimally modified low-density lipoprotein induces macrophage endoplasmic reticulum stress via toll-like receptor 4. Biochim Biophys Acta 1821:954–963. https://doi.org/10.1016/j.bbalip.2012.03.003

    Article  CAS  PubMed  Google Scholar 

  28. Martinon F, Chen X, Lee AH, Glimcher LH (2010) TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol 11:411–418. https://doi.org/10.1038/ni.1857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hamid SM, Citir M, Terzi EM, Cimen I, Yildirim Z, Dogan AE, Kocaturk B, Onat UI, Arditi M, Weber C, Traynor-Kaplan A, Schultz C, Erbay E (2020) Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth. EMBO Rep 21:e51462. https://doi.org/10.15252/embr.202051462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pfeffer MA, Shah AM, Borlaug BA (2019) Heart failure with preserved ejection fraction in perspective. Circ Res 124:1598–1617. https://doi.org/10.1161/circresaha.119.313572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dunlay SM, Roger VL, Redfield MM (2017) Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 14:591–602. https://doi.org/10.1038/nrcardio.2017.65

    Article  PubMed  Google Scholar 

  32. Torrealba N, Navarro-Marquez M, Garrido V, Pedrozo Z, Romero D, Eura Y, Villalobos E, Roa JC, Chiong M, Kokame K, Lavandero S (2017) Herpud1 negatively regulates pathological cardiac hypertrophy by inducing IP3 receptor degradation. Sci Rep 7:13402. https://doi.org/10.1038/s41598-017-13797-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Finsen AV, Ueland T, Sjaastad I, Ranheim T, Ahmed MS, Dahl CP, Askevold ET, Aakhus S, Husberg C, Fiane AE, Lipp M, Gullestad L, Christensen G, Aukrust P, Yndestad A (2014) The homeostatic chemokine CCL21 predicts mortality in aortic stenosis patients and modulates left ventricular remodeling. PLoS ONE 9:e112172. https://doi.org/10.1371/journal.pone.0112172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yang MH, Wang H, Han SN, Jia X, Zhang S, Dai FF, Zhou MJ, Yin Z, Wang TQ, Zang MX, Xue LX (2020) Circular RNA expression in isoproterenol hydrochloride-induced cardiac hypertrophy. Aging (Albany NY) 12:2530–2544. https://doi.org/10.18632/aging.102761

    Article  CAS  PubMed  Google Scholar 

  35. Schiattarella GG, Altamirano F, Tong D, French KM, Villalobos E, Kim SY, Luo X, Jiang N, May HI, Wang ZV, Hill TM, Mammen PPA, Huang J, Lee DI, Hahn VS, Sharma K, Kass DA, Lavandero S, Gillette TG, Hill JA (2019) Nitrosative stress drives heart failure with preserved ejection fraction. Nature 568:351–356. https://doi.org/10.1038/s41586-019-1100-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schiattarella GG, Altamirano F, Kim SY, Tong D, Ferdous A, Piristine H, Dasgupta S, Wang X, French KM, Villalobos E, Spurgin SB, Waldman M, Jiang N, May HI, Hill TM, Luo Y, Yoo H, Zaha VG, Lavandero S, Gillette TG, Hill JA (2021) Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction. Nat Commun 12:1684. https://doi.org/10.1038/s41467-021-21931-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smolgovsky S, Bayer AL, Kaur K, Sanders E, Aronovitz M, Filipp ME, Thorp EB, Schiattarella GG, Hill JA, Blanton RM, Cubillos-Ruiz JR, Alcaide P (2023) Impaired T cell IRE1alpha/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction. J Clin Invest. https://doi.org/10.1172/JCI171874

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ni L, Zhou C, Duan Q, Lv J, Fu X, Xia Y, Wang DW (2011) β-AR blockers suppresses ER stress in cardiac hypertrophy and heart failure. PLoS ONE 6:e27294. https://doi.org/10.1371/journal.pone.0027294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ortega FB, Lavie CJ, Blair SN (2016) Obesity and cardiovascular disease. Circ Res 118:1752–1770. https://doi.org/10.1161/circresaha.115.306883

    Article  CAS  PubMed  Google Scholar 

  40. Binder P, Wang S, Radu M, Zin M, Collins L, Khan S, Li Y, Sekeres K, Humphreys N, Swanton E, Reid A, Pu F, Oceandy D, Guan K, Hille SS, Frey N, Müller OJ, Cartwright EJ, Chernoff J, Wang X, Liu W (2019) Pak2 as a novel therapeutic target for cardioprotective endoplasmic reticulum stress response. Circ Res 124:696–711. https://doi.org/10.1161/circresaha.118.312829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Qu J, Li M, Li D, Xin Y, Li J, Lei S, Wu W, Liu X (2021) Stimulation of sigma-1 receptor protects against cardiac fibrosis by alleviating IRE1 pathway and autophagy impairment. Oxid Med Cell Longev 2021:8836818. https://doi.org/10.1155/2021/8836818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Duan Q, Chen C, Yang L, Li N, Gong W, Li S, Wang DW (2015) MicroRNA regulation of unfolded protein response transcription factor XBP1 in the progression of cardiac hypertrophy and heart failure in vivo. J Transl Med 13:363. https://doi.org/10.1186/s12967-015-0725-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee R, Xu B, Rame JE, Felkin LE, Barton P, Dries DL (2014) Regulated inositol-requiring protein 1-dependent decay as a mechanism of corin RNA and protein deficiency in advanced human systolic heart failure. J Am Heart Assoc 3:e001104. https://doi.org/10.1161/jaha.114.001104

    Article  PubMed  PubMed Central  Google Scholar 

  44. Steiger D, Yokota T, Li J, Ren S, Minamisawa S, Wang Y (2018) The serine/threonine-protein kinase/endoribonuclease IRE1α protects the heart against pressure overload-induced heart failure. J Biol Chem 293:9652–9661. https://doi.org/10.1074/jbc.RA118.003448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang YF, Wang H, Song N, Jiang YH, Zhang J, Meng XW, Feng XM, Liu H, Peng K, Ji FH (2021) Dexmedetomidine attenuates ischemia/reperfusion-induced myocardial inflammation and apoptosis through inhibiting endoplasmic reticulum stress signaling. J Inflamm Res 14:1217–1233. https://doi.org/10.2147/jir.S292263

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wu T, Jiang N, Ji Z, Shi G (2019) The IRE1 signaling pathway is involved in the protective effect of low-dose LPS on myocardial ischemia-reperfusion injury. Life Sci 231:116569. https://doi.org/10.1016/j.lfs.2019.116569

    Article  CAS  PubMed  Google Scholar 

  47. Wang ZV, Deng Y, Gao N, Pedrozo Z, Li DL, Morales CR, Criollo A, Luo X, Tan W, Jiang N, Lehrman MA, Rothermel BA, Lee AH, Lavandero S, Mammen PPA, Ferdous A, Gillette TG, Scherer PE, Hill JA (2014) Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156:1179–1192. https://doi.org/10.1016/j.cell.2014.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liang Y, Liang L, Liu Z, Wang Y, Dong X, Qu L, Gou R, Wang Y, Wang Q, Liu Z, Tang L (2020) Inhibition of IRE1/JNK pathway in HK-2 cells subjected to hypoxia-reoxygenation attenuates mesangial cells-derived extracellular matrix production. J Cell Mol Med 24:13408–13420. https://doi.org/10.1111/jcmm.15964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu D, Liu X, Zhou T, Yao W, Zhao J, Zheng Z, Jiang W, Wang F, Aikhionbare FO, Hill DL, Emmett N, Guo Z, Wang D, Yao X, Chen Y (2016) IRE1-RACK1 axis orchestrates ER stress preconditioning-elicited cytoprotection from ischemia/reperfusion injury in liver. J Mol Cell Biol 8:144–156. https://doi.org/10.1093/jmcb/mjv066

    Article  CAS  PubMed  Google Scholar 

  50. Cai J, Zhang X, Chen P, Li Y, Liu S, Liu Q, Zhang H, Wu Z, Song K, Liu J, Shan B, Liu Y (2022) The ER stress sensor inositol-requiring enzyme 1α in Kupffer cells promotes hepatic ischemia-reperfusion injury. J Biol Chem 298:101532. https://doi.org/10.1016/j.jbc.2021.101532

    Article  CAS  PubMed  Google Scholar 

  51. Feng D, Wang B, Wang L, Abraham N, Tao K, Huang L, Shi W, Dong Y, Qu Y (2017) Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings. J Pineal Res 62(3):e12395

    Article  Google Scholar 

  52. Niu J, Wu Z, Xue H, Zhang Y, Gao Q, Li C, Zhao P (2021) Sevoflurane post-conditioning alleviated hypoxic-ischemic brain injury in neonatal rats by inhibiting endoplasmic reticulum stress-mediated autophagy via IRE1 signalings. Neurochem Int 150:105198. https://doi.org/10.1016/j.neuint.2021.105198

    Article  CAS  PubMed  Google Scholar 

  53. Zou J, Fei Q, Xiao H, Wang H, Liu K, Liu M, Zhang H, Xiao X, Wang K, Wang N (2019) VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy. J Cell Physiol 234:17690–17703. https://doi.org/10.1002/jcp.28395

    Article  CAS  PubMed  Google Scholar 

  54. Carreras-Sureda A, Jana F, Urra H, Durand S, Mortenson DE, Sagredo A, Bustos G, Hazari Y, Ramos-Fernandez E, Sassano ML, Pihan P, van Vliet AR, Gonzalez-Quiroz M, Torres AK, Tapia-Rojas C, Kerkhofs M, Vicente R, Kaufman RJ, Inestrosa NC, Gonzalez-Billault C, Wiseman RL, Agostinis P, Bultynck G, Court FA, Kroemer G, Cardenas JC, Hetz C (2019) Non-canonical function of IRE1alpha determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics. Nat Cell Biol 21:755–767. https://doi.org/10.1038/s41556-019-0329-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Carreras-Sureda A, Zhang X, Laubry L, Brunetti J, Koenig S, Wang X, Castelbou C, Hetz C, Liu Y, Frieden M, Demaurex N (2023) The ER stress sensor IRE1 interacts with STIM1 to promote store-operated calcium entry, T cell activation, and muscular differentiation. Cell Rep 42:113540. https://doi.org/10.1016/j.celrep.2023.113540

    Article  CAS  PubMed  Google Scholar 

  56. Petersen CE, Sun J, Silva K, Kosmach A, Balaban RS, Murphy E (2023) Increased mitochondrial free Ca(2+) during ischemia is suppressed, but not eliminated by, germline deletion of the mitochondrial Ca(2+) uniporter. Cell Rep 42:112735. https://doi.org/10.1016/j.celrep.2023.112735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Stege NM, Eijgenraam TR, Oliveira Nunes Teixeira V, Feringa AM, Schouten EM, Kuster DWD, van der Velden J, Wolters AHG, Giepmans BNG, Makarewich CA, Bassel-Duby R, Olson EN, de Boer RA, Silljé HHW (2023) DWORF extends life span in a PLN-R14del cardiomyopathy mouse model by reducing abnormal sarcoplasmic reticulum clusters. Circ Res 133:1006–1021. https://doi.org/10.1161/circresaha.123.323304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Feyen DAM, Perea-Gil I, Maas RGC, Harakalova M, Gavidia AA, Arthur Ataam J, Wu TH, Vink A, Pei J, Vadgama N, Suurmeijer AJ, Te Rijdt WP, Vu M, Amatya PL, Prado M, Zhang Y, Dunkenberger L, Sluijter JPG, Sallam K, Asselbergs FW, Mercola M, Karakikes I (2021) Unfolded protein response as a compensatory mechanism and potential therapeutic target in PLN R14del cardiomyopathy. Circulation 144:382–392. https://doi.org/10.1161/circulationaha.120.049844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zha X, Yue Y, Dong N, Xiong S (2015) Endoplasmic Reticulum stress aggravates viral myocarditis by raising inflammation through the IRE1-associated NF-κB pathway. Can J Cardiol 31:1032–1040. https://doi.org/10.1016/j.cjca.2015.03.003

    Article  PubMed  Google Scholar 

  60. Åberg F, Byrne CD, Pirola CJ, Männistö V, Sookoian S (2023) Alcohol consumption and metabolic syndrome: clinical and epidemiological impact on liver disease. J Hepatol 78:191–206. https://doi.org/10.1016/j.jhep.2022.08.030

    Article  CAS  PubMed  Google Scholar 

  61. Fernández-Solà J (2020) The effects of ethanol on the heart: alcoholic cardiomyopathy. Nutrients. https://doi.org/10.3390/nu12020572

    Article  PubMed  PubMed Central  Google Scholar 

  62. Li SY, Gilbert SA, Li Q, Ren J (2009) Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stress. J Mol Cell Cardiol 47:247–255. https://doi.org/10.1016/j.yjmcc.2009.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yung HW, Korolchuk S, Tolkovsky AM, Charnock-Jones DS, Burton GJ (2007) Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells. Faseb j 21:872–884. https://doi.org/10.1096/fj.06-6054com

    Article  CAS  PubMed  Google Scholar 

  64. Marek-Iannucci S, Yildirim AD, Hamid SM, Ozdemir AB, Gomez AC, Kocatürk B, Porritt RA, Fishbein MC, Iwawaki T, Noval Rivas M, Erbay E, Arditi M (2022) Targeting IRE1 endoribonuclease activity alleviates cardiovascular lesions in a murine model of kawasaki disease vasculitis. JCI Insight. https://doi.org/10.1172/jci.insight.157203

    Article  PubMed  PubMed Central  Google Scholar 

  65. Porritt RA, Zemmour D, Abe M, Lee Y, Narayanan M, Carvalho TT, Gomez AC, Martinon D, Santiskulvong C, Fishbein MC, Chen S, Crother TR, Shimada K, Arditi M, Noval Rivas M (2021) NLRP3 inflammasome mediates immune-stromal interactions in vasculitis. Circ Res 129:e183–e200. https://doi.org/10.1161/circresaha.121.319153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wakita D, Kurashima Y, Crother TR, Noval Rivas M, Lee Y, Chen S, Fury W, Bai Y, Wagner S, Li D, Lehman T, Fishbein MC, Hoffman HM, Shah PK, Shimada K, Arditi M (2016) Role of interleukin-1 signaling in a mouse model of kawasaki disease-associated abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 36:886–897. https://doi.org/10.1161/atvbaha.115.307072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee Y, Schulte DJ, Shimada K, Chen S, Crother TR, Chiba N, Fishbein MC, Lehman TJ, Arditi M (2012) Interleukin-1β is crucial for the induction of coronary artery inflammation in a mouse model of kawasaki disease. Circulation 125:1542–1550. https://doi.org/10.1161/circulationaha.111.072769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Xu M, Qi Q, Men L, Wang S, Li M, Xiao M, Chen X, Wang S, Wang G, Jia H, Liu C (2020) Berberine protects Kawasaki disease-induced human coronary artery endothelial cells dysfunction by inhibiting of oxidative and endoplasmic reticulum stress. Vascul Pharmacol 127:106660. https://doi.org/10.1016/j.vph.2020.106660

    Article  CAS  PubMed  Google Scholar 

  69. Kerkelä R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916. https://doi.org/10.1038/nm1446

    Article  CAS  PubMed  Google Scholar 

  70. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud RM, Walter P (2009) The unfolded protein response signals through high-order assembly of Ire1. Nature 457:687–693. https://doi.org/10.1038/nature07661

    Article  CAS  PubMed  Google Scholar 

  71. Telli ML, Witteles RM, Fisher GA, Srinivas S (2008) Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 19:1613–1618. https://doi.org/10.1093/annonc/mdn168

    Article  CAS  PubMed  Google Scholar 

  72. Zhang X, Chen C (2012) A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy. Endocrine 41:398–409. https://doi.org/10.1007/s12020-012-9623-1

    Article  CAS  PubMed  Google Scholar 

  73. Kenny HC, Abel ED (2019) Heart failure in type 2 diabetes mellitus. Circ Res 124:121–141. https://doi.org/10.1161/circresaha.118.311371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51:1938–1948. https://doi.org/10.2337/diabetes.51.6.1938

    Article  CAS  PubMed  Google Scholar 

  75. Zou MH, Xie Z (2013) Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK. Autophagy 9:624–625. https://doi.org/10.4161/auto.23577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang S, Duan J, Liao J, Wang Y, Xiao X, Li L, Liu Y, Gu H, Yang P, Fu D, Du J, Li X, Shao M (2022) LncRNA H19 inhibits ER stress induced apoptosis and improves diabetic cardiomyopathy by regulating PI3K/AKT/mTOR axis. Aging (Albany NY) 14:6809–6828. https://doi.org/10.18632/aging.204256

    Article  CAS  PubMed  Google Scholar 

  77. Zeng Z, Wang Q, Yang X, Ren Y, Jiao S, Zhu Q, Guo D, Xia K, Wang Y, Li C, Wang W (2019) Qishen granule attenuates cardiac fibrosis by regulating TGF-β /Smad3 and GSK-3β pathway. Phytomedicine 62:152949. https://doi.org/10.1016/j.phymed.2019.152949

    Article  PubMed  Google Scholar 

  78. Li Y, Li X, Chen X, Sun X, Liu X, Wang G, Liu Y, Cui L, Liu T, Wang W, Wang Y, Li C (2022) Qishen granule (QSG) inhibits monocytes released from the spleen and protect myocardial function via the TLR4-MyD88-NF-κB p65 pathway in heart failure mice. Front Pharmacol 13:850187. https://doi.org/10.3389/fphar.2022.850187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lu W, Wang Q, Sun X, He H, Wang Q, Wu Y, Liu Y, Wang Y, Li C (2019) Qishen granule improved cardiac remodeling via balancing M1 and M2 macrophages. Front Pharmacol 10:1399. https://doi.org/10.3389/fphar.2019.01399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chen X, Li Y, Li J, Liu T, Jiang Q, Hong Y, Wang Q, Li C, Guo D, Wang Y (2022) Qishen granule (QSG) exerts cardioprotective effects by inhibiting NLRP3 inflammasome and pyroptosis in myocardial infarction rats. J Ethnopharmacol 285:114841. https://doi.org/10.1016/j.jep.2021.114841

    Article  CAS  PubMed  Google Scholar 

  81. Zhang J, Li W, Xue S, Gao P, Wang H, Chen H, Hong Y, Sun Q, Lu L, Wang Y, Wang Q (2024) Qishen granule attenuates doxorubicin-induced cardiotoxicity by protecting mitochondrial function and reducing oxidative stress through regulation of Sirtuin3. J Ethnopharmacol 319:117134. https://doi.org/10.1016/j.jep.2023.117134

    Article  CAS  PubMed  Google Scholar 

  82. Zhang Q, Shi J, Guo D, Wang Q, Yang X, Lu W, Sun X, He H, Li N, Wang Y, Li C, Wang W (2020) Qishen granule alleviates endoplasmic reticulum stress-induced myocardial apoptosis through IRE-1-CRYAB pathway in myocardial ischemia. J Ethnopharmacol 252:112573. https://doi.org/10.1016/j.jep.2020.112573

    Article  CAS  PubMed  Google Scholar 

  83. Zhang J, Cheng YJ, Luo CJ, Yu J (2022) Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling. Front Pharmacol 13:940365. https://doi.org/10.3389/fphar.2022.940365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Guo R, Liu W, Liu B, Zhang B, Li W, Xu Y (2015) SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: an insight into endoplasmic reticulum stress response mechanism. Int J Cardiol 191:36–45. https://doi.org/10.1016/j.ijcard.2015.04.245

    Article  PubMed  Google Scholar 

  85. Hou J, Zheng D, Fung G, Deng H, Chen L, Liang J, Jiang Y, Hu Y (2016) Mangiferin suppressed advanced glycation end products (AGEs) through NF-κB deactivation and displayed anti-inflammatory effects in streptozotocin and high fat diet-diabetic cardiomyopathy rats. Can J Physiol Pharmacol 94:332–340. https://doi.org/10.1139/cjpp-2015-0073

    Article  CAS  PubMed  Google Scholar 

  86. Wang S, Wang Z, Fan Q, Guo J, Galli G, Du G, Wang X, Xiao W (2016) Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol-requiring enzyme 1α/X box-binding protein-1 pathway. Br J Pharmacol 173:2402–2418. https://doi.org/10.1111/bph.13516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wu J, Xu X, Li Y, Kou J, Huang F, Liu B, Liu K (2014) Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol 745:59–68. https://doi.org/10.1016/j.ejphar.2014.09.046

    Article  CAS  PubMed  Google Scholar 

  88. Guo XD, Zhang DY, Gao XJ, Parry J, Liu K, Liu BL, Wang M (2013) Quercetin and quercetin-3-O-glucuronide are equally effective in ameliorating endothelial insulin resistance through inhibition of reactive oxygen species-associated inflammation. Mol Nutr Food Res 57:1037–1045. https://doi.org/10.1002/mnfr.201200569

    Article  CAS  PubMed  Google Scholar 

  89. Choy KW, Murugan D, Mustafa MR (2018) Natural products targeting ER stress pathway for the treatment of cardiovascular diseases. Pharmacol Res 132:119–129. https://doi.org/10.1016/j.phrs.2018.04.013

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by Research Grant of Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education (2023MZFS006).

Author information

Author notes

  1. Lu Zhou and Xizi Zhu have been contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China

    Lu Zhou, Xizi Zhu, Shaoqing Lei & Zhongyuan Xia

  2. Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yafeng Wang

  3. Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yafeng Wang

  4. Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, China

    Yafeng Wang

Authors
  1. Lu Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xizi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shaoqing Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yafeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhongyuan Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Lu Zhou, Xizi Zhu and Yafeng Wang drafted the manuscript, Shaoqing Lei revised the manuscript, Zhong-yuan Xia and Yafeng Wang approved the submission. All authors approved the final version of the paper.

Corresponding authors

Correspondence to Yafeng Wang or Zhongyuan Xia.

Ethics declarations

Competing interests

The authors declare that there are no conflicts of interest.

Ethics approval

Not Applicable.

Consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, L., Zhu, X., Lei, S. et al. The role of the ER stress sensor IRE1 in cardiovascular diseases. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-05014-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11010-024-05014-z

Keywords

Search

Navigation