Abstract
The induction of endoplasmic reticulum (ER) stress has been reported as a key contributor to the cardiotoxicity of doxorubicin. Previous in vitro and in vivo studies suggest that sacubitril/valsartan, a novel angiotensin receptor–neprilysin inhibitor, could be effective against doxorubicin-induced cardiotoxicity. However, the precise mechanisms are not fully understood. Therefore, we investigated whether the cardioprotective effects of sacubitril/valsartan are associated with ER stress modulation in a rat model of doxorubicin-induced cardiotoxicity. Male Sprague–Dawley rats were treated with intraperitoneal injections of doxorubicin (15 mg/kg; cumulative) or saline for 3 weeks. From the day before the first treatment, control animals were gavaged daily with water (n = 8), whereas doxorubicin-treated animals were gavaged daily with water (n = 8) or sacubitril/valsartan (60 mg/kg/day; n = 8) for 6 weeks. Echocardiography was performed 6 weeks after the initiation of doxorubicin. In addition, serum troponin I and N-terminal brain natriuretic peptide levels were determined, and the extent of apoptosis and protein levels related to ER stress in the cardiac tissue and doxorubicin-treated H9c2 cardiomyocytes were analyzed. Sacubitril/valsartan significantly reduced doxorubicin-induced cardiac dysfunction and apoptosis in the myocardium. In addition, sacubitril/valsartan significantly downregulated the expression levels of proteins related to apoptosis and ER stress, including BAX, caspase 3, GRP78, PERK, IRE-1α, ATF-6, eIF-2α, ATF-4, and CHOP, in the myocardium of a rat model of doxorubicin-induced cardiotoxicity in vivo and doxorubicin-treated H9c2 cardiomyocytes in vitro. Sacubitril/valsartan significantly alleviated doxorubicin-induced cardiotoxicity, which may be associated with the reduction of ER stress.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The interpreted and analyzed data from this study are available from the corresponding author upon reasonable request.
References
Bhattarai KR, Chaudhary M, Kim H-R, Chae H-J (2020) Endoplasmic reticulum (ER) stress response failure in diseases. Trends Cell Biol 30(9):672–675. https://doi.org/10.1016/j.tcb.2020.05.004
Bosch X, Rovira M, Sitges M et al (2013) Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 61(23):2355–2362. https://doi.org/10.1016/j.jacc.2013.02.072
Boutagy NE, Feher A, Pfau D et al (2020) Dual angiotensin receptor-neprilysin inhibition with sacubitril/valsartan attenuates systolic dysfunction in experimental doxorubicin-induced cardiotoxicity. JACC CardioOncol 2(5):774–787. https://doi.org/10.1016/j.jaccao.2020.09.007
Cardinale D, Colombo A, Bacchiani G et al (2015) Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 131(22):1981–1988. https://doi.org/10.1161/circulationaha.114.013777
Chang P, Zhang M, Zhang X et al (2019) B-type natriuretic peptide attenuates endoplasmic reticulum stress in H9c2 cardiomyocytes underwent hypoxia/reoxygenation injury under high glucose/high fat conditions. Peptides 111:103–111. https://doi.org/10.1016/j.peptides.2018.04.016
Chow EJ, Asselin BL, Schwartz CL et al (2015) Late mortality after Dexrazoxane treatment: a report from the Children’s Oncology Group. J Clin Oncol 33(24):2639–2645. https://doi.org/10.1200/JCO.2014.59.4473
Courreges AP, Najenson AC, Vatta MS, Bianciotti LG (2019) Atrial natriuretic peptide attenuates endoplasmic reticulum stress in experimental acute pancreatitis. Biochim Biophys Acta 2:485–493. https://doi.org/10.1016/j.bbadis.2018.12.004
Fu HY, Sanada S, Matsuzaki T et al (2016) Chemical endoplasmic reticulum chaperone alleviates doxorubicin-induced cardiac dysfunction. Circ Res 118(5):798–809. https://doi.org/10.1161/circresaha.115.307604
Gu J, Noe A, Chandra P et al (2010) Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 50(4):401–414. https://doi.org/10.1177/0091270009343932
Hu H, Tian M, Ding C, Yu S (2018) The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol 9:3083. https://doi.org/10.3389/fimmu.2018.03083
Iurlaro R, Muñoz-Pinedo C (2016) Cell death induced by endoplasmic reticulum stress. FEBS J 283(14):2640–2652. https://doi.org/10.1111/febs.13598
Lee KM, Kang HA, Park M et al (2012) Interleukin-24 attenuates β-glycerophosphate-induced calcification of vascular smooth muscle cells by inhibiting apoptosis, the expression of calcification and osteoblastic markers, and the Wnt/β-catenin pathway. Biochem Biophys Res Commun 428(1):50–55. https://doi.org/10.1016/j.bbrc.2012.09.145
Martín-Garcia A, López-Fernández T, Mitroi C et al (2020) Effectiveness of sacubitril-valsartan in cancer patients with heart failure. ESC Heart Failure 7(2):763–767. https://doi.org/10.1002/ehf2.12627
McDonagh TA, Metra M, Adamo M et al (2021) 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. https://doi.org/10.1093/eurheartj/ehab368
McMurray JJ, Packer M, Desai AS et al (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371(11):993–1004. https://doi.org/10.1056/NEJMoa1409077
Osataphan N, Phrommintikul A, Chattipakorn SC, Chattipakorn N (2020) Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions. J Cell Mol Med 24(12):6534–6557. https://doi.org/10.1111/jcmm.15305
Park IH, Shen GY, Song YS et al (2021) Granulocyte colony-stimulating factor reduces the endoplasmic reticulum stress in a rat model of diabetic cardiomyopathy. Endocr J. https://doi.org/10.1507/endocrj.EJ21-0016
Percie du Sert N, Hurst V, Ahluwalia A et al (2020) The ARRIVE guidelines 20: updated guidelines for reporting animal research. PLoS Biol 18(7):e3000410. https://doi.org/10.1371/journal.pbio.3000410
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(7):499–521. https://doi.org/10.1038/s41569-021-00511-w
Renu K, A VG, Tp PB, Arunachalam S (2018) Molecular mechanism of doxorubicin-induced cardiomyopathy—an update. Eur J Pharmacol 818:241–253. https://doi.org/10.1016/j.ejphar.2017.10.043
Ron D, Habener JF (1992) CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev 6(3):439–453. https://doi.org/10.1101/gad.6.3.439
Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I (2016) The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr Mol Med 16(6):533–544. https://doi.org/10.2174/1566524016666160523143937
Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochem Biophys Acta 1833(12):3460–3470. https://doi.org/10.1016/j.bbamcr.2013.06.028
Shin JH, Lim YH, Song YS et al (2014) Granulocyte-colony stimulating factor reduces cardiomyocyte apoptosis and ameliorates diastolic dysfunction in Otsuka Long-Evans Tokushima Fatty rats. Cardiovasc Drugs Ther 28(3):211–220. https://doi.org/10.1007/s10557-014-6519-8
Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339(13):900–905. https://doi.org/10.1056/nejm199809243391307
Songbo M, Lang H, Xinyong C, Bin X, Ping Z, Liang S (2019) Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett 307:41–48. https://doi.org/10.1016/j.toxlet.2019.02.013
Tebbi CK, London WB, Friedman D et al (2007) Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 25(5):493–500. https://doi.org/10.1200/jco.2005.02.3879
van Dalen EC, Michiels EM, Caron HN (2010) Kremer LC (2010) Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev 5:CD005006. https://doi.org/10.1002/14651858.CD005006.pub4
Xia Y, Chen Z, Chen A et al (2017) LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy. J Mol Cell Cardiol 108:138–148. https://doi.org/10.1016/j.yjmcc.2017.06.003
Yarmohammadi F, Rezaee R, Haye AW, Karimi G (2021) Endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity may be therapeutically targeted by natural and chemical compounds: a review. Pharmacol Res 164:105383. https://doi.org/10.1016/j.phrs.2020.105383
Yeh ET, Bickford CL (2009) Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 53(24):2231–2247. https://doi.org/10.1016/j.jacc.2009.02.050
Zhang S, Liu X, Bawa-Khalfe T et al (2012) Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 18(11):1639–1642. https://doi.org/10.1038/nm.2919
Zhao X, Kong Y, Li S, Liang B, Li C, Wang W (2020) Atrial natriuretic peptide prevented lipid-induced kidney injuries by inhibiting endoplasmic reticulum stress. FASEB J 34(S1):1–1. https://doi.org/10.1096/fasebj.2020.34.s1.02690
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Contributions
Conceptualization: JHS and YHL. Methodology: BSK and IHP. Formal analysis: AHL and HJK. Investigation: IHP and AHL. Data curation: BSK and HJK. Writing—original draft preparation: BSK and IHP. Writing—review and editing: JHS and YHL. Supervision: JHS and YHL.
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no conflicts of interest to declare.
Ethical approval
The research protocol was approved by the Hanyang University Institutional Animal Care and Use Committee.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
204_2022_3241_MOESM2_ESM.jpg
Supplementary Fig. S1 Effects of Dox and Sac/Val on the viability of H9c2 cardiomyocytes The cells were treated with increasing concentrations of (a) Dox (10 nM to 10 μM) or (b) Sac/Val (1 μM to 20 μM). MTT assay was performed to measure cell viability (JPG 166 KB)
Rights and permissions
About this article
Cite this article
Kim, B.S., Park, IH., Lee, AH. et al. Sacubitril/valsartan reduces endoplasmic reticulum stress in a rat model of doxorubicin-induced cardiotoxicity. Arch Toxicol 96, 1065–1074 (2022). https://doi.org/10.1007/s00204-022-03241-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-022-03241-1