Physiological and Pathological Functions of NADPH Oxidases During Myocardial Ischemia-reperfusion

Overview

Journal Trends Cardiovasc Med

Specialty Cardiology & Vascular Diseases

Date 2014 Jun 2

PMID 24880746

Citations 70

Authors

Shouji Matsushima

Hiroyuki Tsutsui

Junichi Sadoshima

Affiliations

Soon will be listed here.

Abstract

Oxidative stress, the presence of reactive oxygen species (ROS) in excess of the antioxidant capacity in the heart induces myocardial damage, accumulation of which leads to ischemic heart disease and heart failure. NADPH oxidase (Nox) 2 and 4 are the major sources of O2- and H2O2 in the heart and play a crucial role in the regulation of growth and death in cardiomyocytes. Both Nox2 and Nox4 are upregulated in response to ischemia-reperfusion (I/R), thereby contributing to ROS production and consequent myocardial injury. Suppression of either one of them can reduce ROS and I/R injury in the heart. Importantly, however, a minimum level of ROS production by either Nox2 or Nox4 is essential for the activation of HIF-1α and inhibition of PPARα during I/R, such that combined suppression of both Nox2 and Nox4 exacerbates myocardial I/R injury. Thus, either excessive activation or suppression of Noxs below physiological levels can induce cardiac injury. Here we discuss both detrimental and salutary functions of Nox isoforms during myocardial I/R.

Citing Articles

In defence of ferroptosis.

Alves F, Lane D, Nguyen T, Bush A, Ayton S Signal Transduct Target Ther. 2025; 10(1):2.

PMID: 39746918 PMC: 11696223. DOI: 10.1038/s41392-024-02088-5.

Specific NOX4 Inhibition Preserves Mitochondrial Function and Dampens Kidney Dysfunction Following Ischemia-Reperfusion-Induced Kidney Injury.

Schiffer T, Carvalho L, Guimaraes D, Boeder A, Wikstrom P, Carlstrom M Antioxidants (Basel). 2024; 13(4).

PMID: 38671936 PMC: 11047485. DOI: 10.3390/antiox13040489.

Knockdown of ANGPTL2 promotes left ventricular systolic dysfunction by upregulation of NOX4 in mice.

Labbe P, Martel C, Shi Y, Montezano A, He Y, Gillis M Front Physiol. 2024; 15:1320065.

PMID: 38426206 PMC: 10902461. DOI: 10.3389/fphys.2024.1320065.

Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium.

Harris D, Sabe S, Broadwin M, Xu C, Stone C, Kanuparthy M Bioengineering (Basel). 2024; 11(2).

PMID: 38391611 PMC: 10886197. DOI: 10.3390/bioengineering11020125.

Cardiac endothelial ischemia/reperfusion injury-derived protein damage-associated molecular patterns disrupt the integrity of the endothelial barrier.

Kumphune S, Seenak P, Paiyabhrom N, Songjang W, Pankhong P, Jumroon N Heliyon. 2024; 10(2):e24600.

PMID: 38312663 PMC: 10835233. DOI: 10.1016/j.heliyon.2024.e24600.

References

Ago T, Kuroda J, Pain J, Fu C, Li H, Sadoshima J . Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ Res. 2010; 106(7):1253-64. PMC: 2855780. DOI: 10.1161/CIRCRESAHA.109.213116. View

Tazzeo T, Worek F, Janssen L . The NADPH oxidase inhibitor diphenyleneiodonium is also a potent inhibitor of cholinesterases and the internal Ca(2+) pump. Br J Pharmacol. 2009; 158(3):790-6. PMC: 2765598. DOI: 10.1111/j.1476-5381.2009.00394.x. View

Matsuno K, Iwata K, Matsumoto M, Katsuyama M, Cui W, Murata A . NOX1/NADPH oxidase is involved in endotoxin-induced cardiomyocyte apoptosis. Free Radic Biol Med. 2012; 53(9):1718-28. DOI: 10.1016/j.freeradbiomed.2012.08.590. View

Jiang J, Chen X, Serizawa N, Szyndralewiez C, Page P, Schroder K . Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med. 2012; 53(2):289-96. PMC: 3392471. DOI: 10.1016/j.freeradbiomed.2012.05.007. View

Lyle A, Deshpande N, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P . Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res. 2009; 105(3):249-59. PMC: 2744198. DOI: 10.1161/CIRCRESAHA.109.193722. View

Kleinschnitz C, Grund H, Wingler K, Armitage M, Jones E, Mittal M . Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010; 8(9). PMC: 2943442. DOI: 10.1371/journal.pbio.1000479. View

Hoffmeyer M, Jones S, Ross C, Sharp B, Grisham M, Laroux F . Myocardial ischemia/reperfusion injury in NADPH oxidase-deficient mice. Circ Res. 2000; 87(9):812-7. DOI: 10.1161/01.res.87.9.812. View

Gerald D, Berra E, Frapart Y, Chan D, Giaccia A, Mansuy D . JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell. 2004; 118(6):781-94. DOI: 10.1016/j.cell.2004.08.025. View

Looi Y, Grieve D, Siva A, Walker S, Anilkumar N, Cave A . Involvement of Nox2 NADPH oxidase in adverse cardiac remodeling after myocardial infarction. Hypertension. 2008; 51(2):319-25. DOI: 10.1161/HYPERTENSIONAHA.107.101980. View

10.

Maejima Y, Kuroda J, Matsushima S, Ago T, Sadoshima J . Regulation of myocardial growth and death by NADPH oxidase. J Mol Cell Cardiol. 2011; 50(3):408-16. PMC: 3257581. DOI: 10.1016/j.yjmcc.2010.12.018. View

11.

Matsushima S, Kuroda J, Ago T, Zhai P, Ikeda Y, Oka S . Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α. Circ Res. 2013; 112(8):1135-49. PMC: 3871171. DOI: 10.1161/CIRCRESAHA.111.300171. View

12.

Stolk J, Hiltermann T, Dijkman J, Verhoeven A . Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am J Respir Cell Mol Biol. 1994; 11(1):95-102. DOI: 10.1165/ajrcmb.11.1.8018341. View

13.

Heumuller S, Wind S, Barbosa-Sicard E, Schmidt H, Busse R, Schroder K . Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant. Hypertension. 2007; 51(2):211-7. DOI: 10.1161/HYPERTENSIONAHA.107.100214. View

14.

Niethammer P, Grabher C, Look A, Mitchison T . A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature. 2009; 459(7249):996-9. PMC: 2803098. DOI: 10.1038/nature08119. View

15.

Kuroda J, Ago T, Matsushima S, Zhai P, Schneider M, Sadoshima J . NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci U S A. 2010; 107(35):15565-70. PMC: 2932625. DOI: 10.1073/pnas.1002178107. View

16.

Zhang M, Brewer A, Schroder K, Santos C, Grieve D, Wang M . NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci U S A. 2010; 107(42):18121-6. PMC: 2964252. DOI: 10.1073/pnas.1009700107. View

17.

Sancho P, Fabregat I . The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells. Biochem Pharmacol. 2011; 81(7):917-24. DOI: 10.1016/j.bcp.2011.01.007. View

18.

Schroder K, Zhang M, Benkhoff S, Mieth A, Pliquett R, Kosowski J . Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res. 2012; 110(9):1217-25. DOI: 10.1161/CIRCRESAHA.112.267054. View

19.

Matsushima S, Kuroda J, Ago T, Zhai P, Park J, Xie L . Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy. Circ Res. 2012; 112(4):651-63. PMC: 3574183. DOI: 10.1161/CIRCRESAHA.112.279760. View

20.

Grieve D, Byrne J, Siva A, Layland J, Johar S, Cave A . Involvement of the nicotinamide adenosine dinucleotide phosphate oxidase isoform Nox2 in cardiac contractile dysfunction occurring in response to pressure overload. J Am Coll Cardiol. 2006; 47(4):817-26. DOI: 10.1016/j.jacc.2005.09.051. View