Effects of ivabradine on myocardial autophagia and apoptosis in isoprenaline-induced heart failure in mice

Document Type : Original Article

Authors

1 Department of Cardiology, Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China

2 The University of Sydney, Newtown, NSW 2042, Australia

3 Department of Geriatric Cardiology, Guangdong Provincial People’s Hospital, Guangzhou, PR. China, 510080

Abstract

Objective(s): To investigate the effects and mechanisms of ivabradine (IVA) on isoprenaline-induced cardiac injury.
Materials and Methods: Forty male C57BL/6 mice were randomly divided into control group, model group, high-dose IVA group, and low-dose IVA group. The control group was given saline, other groups were given subcutaneous injections of isoproterenol (ISO) 5 mg/kg/d to make the myocardial remodeling model. A corresponding dose of IVA (high dose 50 mg/kg/d, low dose 10 mg/kg/d) was given by gavage (30 days). A transthoracic echocardiogram was obtained to detect the structure and function of the heart. An electron microscope was used to explore the cardiomyocytes’ apoptosis and autophagy. HE staining and Masson’s trichrome staining were performed to explore myocardial hypertrophy and fibrosis. Western blot was used to detect Bax, Bcl-2, cleaved caspase-3, Becline-1, LC3, phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), phosphorylated extracellular regulated protein kinases1/2 (p-ERK1/2), phosphorylated c-Jun N-terminal kinase (p-JNK), and α-smooth muscle actin (α-SMA) in the myocardium.
Results: Heart rate in the IVA groups was reduced, and the trend of heart rate reduction was more obvious in the high-dose group. Echocardiography showed that IVA improved the cardiac structure and function compared to the model group. IVA attenuated cardiac fibrosis, decreased cardiomyocyte apoptosis, and increased autophagy. The phosphorylated MAPK in the ISO-induced groups was increased. IVA treatment decreased the p-p38MAPK level. There were no differences in p-ERK and p-JNK levels.
Conclusion: The beneficial effects of IVA on myocardial injury are related to blocking the p38MAPK signal pathway, decreasing cardiomyocyte apoptosis, and increasing cardiomyocyte autophagy.

Keywords

Main Subjects

References

1. Díez-Villanueva P, Jiménez-Méndez C, Alfonso F. Heart failure in the elderly. J Geriatr Cardiol 2021; 18: 219-232. 
2. Bertero E, Robusto F, Rulli E, D’Ettorre A, Bisceglia L, Staszewsky L, et al. Cancer incidence and mortality according to pre-existing heart failure in a community-based cohort. JACC CardioOncol 2022; 4: 98-109. 
3. Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart failure with reduced ejection fraction: A review. JAMA 2020; 324: 488-504.
4. Gulati G, Udelson JE. Heart failure with improved ejection fraction: Is it possible to escape one’s past? JACC Heart Fail 2018; 6: 725-733.
5. Kotecha D, Flather MD, Altman DG, Holmes J, Rosano G, Wikstrand J, et al. Heart rate and rhythm and the benefit of beta-blockers in patients with heart failure. J Am Coll Cardiol 2017; 69: 2885-2896. 
6. Kharouf Q, Phillips AM, Bleakley LE, Morrisroe E, Oyrer J, Jia L, et al. The hyperpolarization-activated cyclic nucleotide-gated 4 channel as a potential anti-seizure drug target. Br J Pharmacol 2020; 177: 3712-3729. 
7. Depuydt AS, Peigneur S, Tytgat J. HCN channels in the heart. Curr Cardiol Rev 2022; 18: e040222200836.
Heusch, G, Klenibongard P. Ivabradine: Cardiopretection by and beyond heart rate reduction. Drugs 2016; 76: 733-740. 
Chen C, Kaur G, Mehta PK, Morrone D, Godoy LC, Bangalore S, et al. Ivabradine in cardiovascular disease management revisited: A review. Cardiovasc Drugs Ther 2021; 35: 1045-1056.
10. Tardif JC, Ponikowski P, Kahan Thomas, Associate Study Investigators. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J 2009; 30: 540-548.
11. Gammone MA, Riccioni G, Massari F, D’Orazio N. Beneficial effect of ivabradine against cardiovascular diseases. Front Biosci (Schol Ed) 2020; 12: 161-172. 
12. Riccioni G. Ivabradine: An intelligent drug for the treatment of ischemic heart disease. Molecules 2012; 17: 13592-13604. 
13. Ennezat PV, Cosgrove S, Marechaux S, Bouvaist H, Le Jemtel TH, et al. Limited role and benefit of ivabradine in the treatment of angina and heart failure with reduced ejection fraction. Acta Cardiol 2017; 72: 664-668.
14. Kleinbongard P, Gedik N, Witting P, Freedman B, Klöcker N, Heusch G. Pleiotropic, heart rate-independent cardioprotection by ivabradine. Br J Pharmacol 2015; 172: 4380-4390.
15. Vaillant F, Dehina L, Mazzadi A, Descotes J, Chevalier P, Tabib A, et al. Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: Role of myocyte structure and myocardial perfusion. Resuscitation 2011; 82: 1092-1099.
16. Xue Q, Wang X, Wang P, Zhang K, Liu Q. Role of p38MAPK in apoptosis and autophagy responses to photodynamic therapy with Chlorin e6. Photodiagnosis Photodyn Ther 2015; 12: 84-91.
17. Seong JB, Bae YC, Lee HS, Huh JW, Lee SR, Lee HJ, et al. Increasing ERK phosphorylation by inhibition of p38 activity protects against cadmium-induced apoptotic cell death through ERK/Drp1/p38 signaling axis in spermatocyte-derived GC-2spd cells. Toxicol Appl Pharmacol 2019; 384: 114797-114815.
18. Fu Y, Xiao H, Zhang Y. Beta-adrenoceptor signaling pathways mediated cardiac pathological remodeling. Front Biosci (Elite Ed) 2012; 4: 1625-1637.
19. Khoynezhad A, Jalali Z, Tortolani AJ. A synopsis of research in cardiac apoptosis and its application to congestive heart failure. Tex Heart Inst J 2007; 34: 352-359. 
20. Fonfara S, Kitz S, Monteith G, Hahn S, Kipar A. Myocardial transcription of inflammatory and remodeling markers in cats with hypertrophic cardiomyopathy and systemic diseases associated with an inflammatory phenotype. Res Vet Sci 2021; 136: 484-494.
21. Estaquier J, Vallette F, Vayssiere JL, Mignotte B. The mitochondrial pathways of apoptosis. Adv Exp Med Biol 2012; 942: 157-83.
22. Mignotte B, Vayssiere JL. Mitochondria and apoptosis. Eur J Biochem 1998; 252: 1-15. 
23. Brancolini C, Lazarevic D, Rodriguez J, Schneider C. Dismantling cell-cell contacts during apoptosis is coupled to a caspase-dependent proteolytic cleavage of beta-catenin. J Cell Biol 1997; 139: 759-771.
24. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 2007;13:619-624.
25. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 2016; 97: 245-262. 
26. Wu XY, Luo AY, Zhuo YR, Ren JH. N-acetylcysteine reduces oxidative stress, nuclear factor-κB activity and cardiomyocyte apoptosis in heart failure. Mol Med Rep 2014; 10: 615-624.
27. Thandavarayan RA, Watanabe K, Ma M, Gurusamy N, Veeraveedu PT, Konishi T, et al. Dominant-negative p38 mitogen-activated protein kinase prevents cardiac apoptosis and remodeling after streptozotocin-induced diabetes mellitus. Am J Physiol Heart Circ Physiol 2009; 297: H911-919.
28. Sui XB, Kong N, Ye L, Han WD, Zhou JC, Zhang Q, et al. p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett 2014; 344: 174-179.
29. Balcazar D, Regge V, Santalla M, Meyer H, Paululat A, Mattiazzi A, et al. SERCA is critical to control the Bowditch effect in the heart. Sci Rep 2018; 8: 12447-12454. 
30. Gierula J, Paton MF, Lowry JE, Jamil HA, Byrom R, Drozd M, et al. Rate-response programming tailored to the force-frequency relationship improves exercise tolerance in chronic heart failure. JACC Heart Fail 2018; 6: 105-113. 
31. Han Q, Zhang C, You S, Zheng D, Zhong C, Dong H, et al. Resting heart rate and in-hospital mortality in acute ischemic stroke patients with and without atrial fibrillation. Circ J 2020; 84: 656-661.
32. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet. 2010; 376: 875-885.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 1
January 2024
Pages 107-113

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