Neuregulin-1 Suppresses Cardiomyocyte Apoptosis by Activating PI3K/Akt and Inhibiting Mitochondrial Permeability Transition Pore

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2012 Aug 14

PMID 22886427

Citations 20

Authors

Bingzhang Jie

Xiaoxia Zhang

Xuesi Wu

Yi Xin

Yong Liu

Yongfang Guo

Affiliations

Soon will be listed here.

Abstract

Neuregulin-1 (NRG-1) has been shown to attenuate cardiomyocyte apoptosis but the underlying signaling mechanism remains elusive. In this study, we focused on mitochondrial permeability transition pore (mPTP) opening and PI3K/Akt pathway to investigate the effects of NRG-1 on oxidative stress-induced apoptosis of cardiomyocyte. Human cardiac myocytes and neonatal rat cardiac myocytes were exposed to hydrogen peroxide with or without pre-treatment with recombinant human neuregulin-1 (rhNRG-1). Cell apoptosis and mPTP opening were assayed by flow cytometry and confocal microscopy. The activation of Akt was detected by western blot analysis. The results showed that H(2)O(2) induced cardiomyocyte apoptosis and activated mPTP. rhNRG-1 inhibited mPTP and activated Akt in the presence of H(2)O(2) and further protected the cells from H(2)O(2)-induced apoptosis. However, rhNRG-1 failed to inhibit mPTP opening and cell apoptosis in the presence of PI3K inhibitor LY294002. Taken together, these findings suggest that NRG-1 activates PI3K/Akt signaling and inhibits mPTP opening, and downstream apoptotic events in cardiac myocytes subjected to oxidative stress.

Citing Articles

Small-molecule-induced ERBB4 activation to treat heart failure.

Cools J, Goovaerts B, Feyen E, Van den Bogaert S, Fu Y, Civati C Nat Commun. 2025; 16(1):576.

PMID: 39794341 PMC: 11724075. DOI: 10.1038/s41467-024-54908-5.

Comparative Serum Proteome Profiling of Canine Benign Prostatic Hyperplasia before and after Castration.

Ploypetch S, Wongbandue G, Roytrakul S, Phaonakrop N, Prapaiwan N Animals (Basel). 2023; 13(24).

PMID: 38136890 PMC: 10740436. DOI: 10.3390/ani13243853.

STAT5b is a key effector of NRG-1/ERBB4-mediated myocardial growth.

Vaparanta K, Jokilammi A, Paatero I, Merilahti J, Heliste J, Hemanthakumar K EMBO Rep. 2023; 24(5):e56689.

PMID: 37009825 PMC: 10157316. DOI: 10.15252/embr.202256689.

PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications.

Xu Z, Gao Z, Fu H, Zeng Y, Jin Y, Xu B Cardiovasc Res. 2023; 119(5):1250-1264.

PMID: 36651911 PMC: 10202646. DOI: 10.1093/cvr/cvad012.

Hypoxia pretreatment improves the therapeutic potential of bone marrow mesenchymal stem cells in hindlimb ischemia via upregulation of NRG-1.

Peng X, Liang B, Wang H, Hou J, Yuan Q Cell Tissue Res. 2022; 388(1):105-116.

PMID: 35091805 DOI: 10.1007/s00441-021-03562-0.

References

Baregamian N, Song J, Jeschke M, Evers B, Chung D . IGF-1 protects intestinal epithelial cells from oxidative stress-induced apoptosis. J Surg Res. 2006; 136(1):31-7. PMC: 2613687. DOI: 10.1016/j.jss.2006.04.028. View

Remondino A, Kwon S, Communal C, Pimentel D, Sawyer D, Singh K . Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res. 2003; 92(2):136-8. DOI: 10.1161/01.res.0000054624.03539.b4. View

Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V . Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003; 107(7):984-91. DOI: 10.1161/01.cir.0000051865.66123.b7. View

Jabbour A, Hayward C, Keogh A, Kotlyar E, McCrohon J, England J . Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur J Heart Fail. 2010; 13(1):83-92. DOI: 10.1093/eurjhf/hfq152. View

Zhao Y, Sawyer D, Baliga R, Opel D, Han X, Marchionni M . Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem. 1998; 273(17):10261-9. DOI: 10.1074/jbc.273.17.10261. View

Vessey D, Li L, Kelley M . Ischemic preconditioning requires opening of pannexin-1/P2X(7) channels not only during preconditioning but again after index ischemia at full reperfusion. Mol Cell Biochem. 2011; 351(1-2):77-84. DOI: 10.1007/s11010-011-0713-9. View

Ky B, Kimmel S, Safa R, Putt M, Sweitzer N, Fang J . Neuregulin-1 beta is associated with disease severity and adverse outcomes in chronic heart failure. Circulation. 2009; 120(4):310-7. PMC: 2741393. DOI: 10.1161/CIRCULATIONAHA.109.856310. View

Rahman S, Li J, Bopassa J, Umar S, Iorga A, Partownavid P . Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury. Anesthesiology. 2011; 115(2):242-53. PMC: 3322241. DOI: 10.1097/ALN.0b013e318223b8b9. View

Petronilli V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P . Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J. 1999; 76(2):725-34. PMC: 1300077. DOI: 10.1016/S0006-3495(99)77239-5. View

10.

Goto K, Takemura G, Maruyama R, Nakagawa M, Tsujimoto A, Kanamori H . Unique mode of cell death in freshly isolated adult rat ventricular cardiomyocytes exposed to hydrogen peroxide. Med Mol Morphol. 2009; 42(2):92-101. DOI: 10.1007/s00795-009-0439-x. View

11.

Eto K, Hommyo A, Yonemitsu R, Abe S . ErbB4 signals Neuregulin1-stimulated cell proliferation and c-fos gene expression through phosphorylation of serum response factor by mitogen-activated protein kinase cascade. Mol Cell Biochem. 2010; 339(1-2):119-25. DOI: 10.1007/s11010-009-0375-z. View

12.

Predescu S, Predescu D, Knezevic I, Klein I, Malik A . Intersectin-1s regulates the mitochondrial apoptotic pathway in endothelial cells. J Biol Chem. 2007; 282(23):17166-78. DOI: 10.1074/jbc.M608996200. View

13.

Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S . Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. Cardiovasc Res. 2010; 87(4):656-64. PMC: 2920811. DOI: 10.1093/cvr/cvq148. View

14.

Chen Q, Chai Y, Mazumder S, Jiang C, Macklis R, Chisolm G . The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death Differ. 2003; 10(3):323-34. PMC: 1196205. DOI: 10.1038/sj.cdd.4401148. View

15.

Kroemer G, Galluzzi L, Brenner C . Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007; 87(1):99-163. DOI: 10.1152/physrev.00013.2006. View

16.

Bopassa J, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M . PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res. 2005; 69(1):178-85. DOI: 10.1016/j.cardiores.2005.07.014. View

17.

Yarden Y, Sliwkowski M . Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001; 2(2):127-37. DOI: 10.1038/35052073. View

18.

Moore X, Tan S, Lo C, Fang L, Su Y, Gao X . Relaxin antagonizes hypertrophy and apoptosis in neonatal rat cardiomyocytes. Endocrinology. 2007; 148(4):1582-9. DOI: 10.1210/en.2006-1324. View

19.

Kuramochi Y, Cote G, Guo X, LeBrasseur N, Cui L, Liao R . Cardiac endothelial cells regulate reactive oxygen species-induced cardiomyocyte apoptosis through neuregulin-1beta/erbB4 signaling. J Biol Chem. 2004; 279(49):51141-7. DOI: 10.1074/jbc.M408662200. View

20.

Garratt A . "To erb-B or not to erb-B..." Neuregulin-1/ErbB signaling in heart development and function. J Mol Cell Cardiol. 2006; 41(2):215-8. DOI: 10.1016/j.yjmcc.2006.05.020. View