SUZ12-Increased NRF2 Alleviates Cardiac Ischemia/Reperfusion Injury by Regulating Apoptosis, Inflammation, and Ferroptosis

Overview

Journal Cardiovasc Toxicol

Specialties Cardiology & Vascular Diseases
Toxicology

Date 2024 Dec 27

PMID 39729180

Authors

Guoyong Zhang

Zhimin Ma

Zheng Ma

Peilin Liu

Lin Zhang

Zheng Lian

Caixia Guo

Affiliations

Soon will be listed here.

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-sensitive transcriptional factor that enables cells to resist oxidant responses, ferroptosis and inflammation. Here, we set out to probe the effects of NRF2 on cardiomyocyte injury under acute myocardial infarction (AMI) condition and its potential mechanism. Human cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to induce cell injury. qRT-PCR and western blot assays were used to detect the levels of mRNAs and proteins. Cardiomyocyte injury was determined by detecting the levels of lactate dehydrogenase and creatine Kinase MB (CK-MB). Cell apoptosis was investigated by flow cytometry and related markers. Levels of IL-6, IL-10, and TNF-α were measured by ELISA. Cell ferroptosis was assessed by detecting the production of reactive oxygen species (ROS), malonaldehyde (MDA), reduced glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio, Fe + content, and related regulators. The interaction between NRF2 and the suppressor of zest 12 (SUZ12) was analyzed by using dual-luciferase reporter and RNA immunoprecipitation assays. AMI rat models were established for in vivo analysis. NRF2 was lowly expressed in AMI patients and H/R-induced cardiomyocytes. Forced expression of NRF2 reduced H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis. Moreover, NRF2 overexpression improved cardiac function and injury in vivo. Mechanistically, SUZ12 bound to the promoter of NRF2 and promoted its expression. Further functional analyses showed that SUZ12 overexpression reduced H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis, which were reversed by NRF2 silencing. SUZ12-increased NRF2 suppressed H/R-induced cardiomyocyte injury, apoptosis, inflammation, and ferroptosis in vitro and improved cardiac functions in rats with I/R injury, suggesting the potential cardioprotective effect of NRF2 in cardiac injury during AMI.

Citing Articles

Temporal Transcriptomic Analysis of Periodontal Disease Progression and Its Molecular Links to Systemic Diseases.

Nantakeeratipat T, Fujihara C, Takedachi M Int J Mol Sci. 2025; 26(5).

PMID: 40076622 PMC: 11900451. DOI: 10.3390/ijms26051998.

The cardio-oncologic burden of breast cancer: molecular mechanisms and importance of preclinical models.

Brauer J, Tumani M, Frey N, Lehmann L Basic Res Cardiol. 2024; 120(1):91-112.

PMID: 39621070 PMC: 11790711. DOI: 10.1007/s00395-024-01090-w.

References

Krittanawong C, Khawaja M, Tamis-Holland J, Girotra S, Rao S . Acute Myocardial Infarction: Etiologies and Mimickers in Young Patients. J Am Heart Assoc. 2023; 12(18):e029971. PMC: 10547302. DOI: 10.1161/JAHA.123.029971. View

Saito Y, Oyama K, Tsujita K, Yasuda S, Kobayashi Y . Treatment strategies of acute myocardial infarction: updates on revascularization, pharmacological therapy, and beyond. J Cardiol. 2022; 81(2):168-178. DOI: 10.1016/j.jjcc.2022.07.003. View

Mao Z, Lin H, Hou J, Zhou Q, Wang Q, Chen Y . A Meta-Analysis of Resveratrol Protects against Myocardial Ischemia/Reperfusion Injury: Evidence from Small Animal Studies and Insight into Molecular Mechanisms. Oxid Med Cell Longev. 2019; 2019:5793867. PMC: 6512035. DOI: 10.1155/2019/5793867. View

Hernandez-Resendiz S, Chinda K, Ong S, Cabrera-Fuentes H, Zazueta C, Hausenloy D . The Role of Redox Dysregulation in the Inflammatory Response to Acute Myocardial Ischaemia-reperfusion Injury - Adding Fuel to the Fire. Curr Med Chem. 2017; 25(11):1275-1293. DOI: 10.2174/0929867324666170329100619. View

Xiang Q, Yi X, Zhu X, Wei X, Jiang D . Regulated cell death in myocardial ischemia-reperfusion injury. Trends Endocrinol Metab. 2023; 35(3):219-234. DOI: 10.1016/j.tem.2023.10.010. View

Feng Y, Zhao J, Hou H, Zhang H, Jiao Y, Wang J . WDR26 promotes mitophagy of cardiomyocytes induced by hypoxia through Parkin translocation. Acta Biochim Biophys Sin (Shanghai). 2016; 48(12):1075-1084. DOI: 10.1093/abbs/gmw104. View

Zhou H, Li D, Zhu P, Ma Q, Toan S, Wang J . Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury. J Pineal Res. 2018; 65(3):e12503. DOI: 10.1111/jpi.12503. View

Li W, Li W, Leng Y, Xiong Y, Xia Z . Ferroptosis Is Involved in Diabetes Myocardial Ischemia/Reperfusion Injury Through Endoplasmic Reticulum Stress. DNA Cell Biol. 2019; 39(2):210-225. DOI: 10.1089/dna.2019.5097. View

Shao L, Shen Y, Ren C, Kobayashi S, Asahara T, Yang J . Inflammation in myocardial infarction: roles of mesenchymal stem cells and their secretome. Cell Death Discov. 2022; 8(1):452. PMC: 9646912. DOI: 10.1038/s41420-022-01235-7. View

10.

Alam M, Kishino A, Sung E, Sekine H, Abe T, Murakami S . Contribution of NRF2 to sulfur metabolism and mitochondrial activity. Redox Biol. 2023; 60:102624. PMC: 9941419. DOI: 10.1016/j.redox.2023.102624. View

11.

Chen G, Liu G, Cao D, Jin M, Guo D, Yuan X . Polydatin protects against acute myocardial infarction-induced cardiac damage by activation of Nrf2/HO-1 signaling. J Nat Med. 2018; 73(1):85-92. DOI: 10.1007/s11418-018-1241-7. View

12.

Strom J, Chen Q . Loss of Nrf2 promotes rapid progression to heart failure following myocardial infarction. Toxicol Appl Pharmacol. 2017; 327:52-58. DOI: 10.1016/j.taap.2017.03.025. View

13.

Wang L, He C . Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front Immunol. 2022; 13:967193. PMC: 9411667. DOI: 10.3389/fimmu.2022.967193. View

14.

Chen L, Zhang Y, Wu Z, Hsieh C, Chu C, Wung B . Peanut arachidin-1 enhances Nrf2-mediated protective mechanisms against TNF-α-induced ICAM-1 expression and NF-κB activation in endothelial cells. Int J Mol Med. 2017; 41(1):541-547. DOI: 10.3892/ijmm.2017.3238. View

15.

Friedmann Angeli J, Krysko D, Conrad M . Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019; 19(7):405-414. DOI: 10.1038/s41568-019-0149-1. View

16.

Yamada N, Karasawa T, Wakiya T, Sadatomo A, Ito H, Kamata R . Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis. Am J Transplant. 2020; 20(6):1606-1618. DOI: 10.1111/ajt.15773. View

17.

Zhao T, Yu Z, Zhou L, Wang X, Hui Y, Mao L . Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice. Cell Death Discov. 2022; 8(1):380. PMC: 9452542. DOI: 10.1038/s41420-022-01173-4. View

18.

Liu X, Chen C, Han D, Zhou W, Cui Y, Tang X . SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity. Oxid Med Cell Longev. 2022; 2022:3192607. PMC: 9225845. DOI: 10.1155/2022/3192607. View

19.

Margueron R, Reinberg D . The Polycomb complex PRC2 and its mark in life. Nature. 2011; 469(7330):343-9. PMC: 3760771. DOI: 10.1038/nature09784. View

20.

Comet I, Riising E, LeBlanc B, Helin K . Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer. 2016; 16(12):803-810. DOI: 10.1038/nrc.2016.83. View