Ameliorative potential of astaxanthin in isoproterenol-induced heart failure in rats via the regulation of the renin-angiotensin system.

Potencial mejorador de la astaxantina en la insuficiencia cardíaca inducida por isoproterenol en ratas a través de la regulación del sistema renina-angiotensina.

• Liang Chang Department of Cardiology, Xi’an Daxing Hospital, Xi’an, Shaanxi Province, China. https://orcid.org/0009-0003-2808-3522
• Furong Qiao Department of Cardiology, Xi’an Daxing Hospital, Xi’an, Shaanxi Province, China. https://orcid.org/0009-0008-7478-1109

DOI: https://doi.org/10.54817/IC.v67n1a09

Keywords: Angiotensin-Converting Enzyme, Arterial Pressure, Endomyocardial Fibrosis, Lactate Dehydrogenase, Renin

Abstract

Heart failure (HF) is a condition in which the heart cannot pump blood effectively to the body. Isoproterenol (ISO) induces HF in rodents by affecting the renin-angiotensin system (RAS). Astaxanthin (AST) is known to have protective effects on the cardiovascular system. However, clear evidence showing that AST improves HF through RAS regulation has not yet been report- ed. This study aimed to investigate the role of AST in ISO-induced HF in rats. HF was induced by intraperitoneal (i.p.) injection of ISO (5 mg/kg/day) for seven consecutive days. AST (25 and 50 mg/kg), aliskiren (30 mg/kg), ramipril (4 mg/kg), and telmisartan (8 mg/kg) were administered orally for 21 days, starting from the last dose of ISO (day 8). Changes in systolic and diastolic blood pressure and heart rate associated with HF were measured on days 0, 7, 14, 21, and 28. Additionally, changes in heart-to-body weight ratio, serum creatine kinase-MB (CK-MB), serum angiotensin-converting enzyme (ACE) ac- tivity, plasma renin activity (PRA), tissue hydroxyproline, and lactate dehydro- genase (LDH) activity, along with histopathological alterations, were evaluated. The administration of AST and RAS-modulating agents reduced ISO-induced changes in cardiac function and biochemical markers. It also demonstrated car- dioprotective effects. Therefore, AST may be useful for treating cardiotoxic HF due to its RAS-regulatory actions. However, further studies are needed to con- firm this therapeutic potential across different HF models and animal species.

References

He X, Huang S, Yu C, Chen Y, Zhu H, Li J, et al. Mst1/Hippo signaling pathway drives isoproterenol-induced inflammatory heart remodeling. Int J Med Sci. 2024;21(9):1718-1729. https://doi.org/10.7150/ijms.95850.

Bozkurt B, Ahmad T, Alexander K, Baker WL, Bosak K, Breathett K, et al. HF STATS 2024: Heart Failure Epidemiology and Outcomes Statistics an Updated 2024 Report from the Heart Failure Society of America. J Card Fail. 2025;31(1):66-116. https://doi.org/10.1016/j.cardfail.2024.07.001.

Perez-Bonilla P, LaViolette B, Bhandary B, Ullas S, Chen X, Hirenallur-Shanthappa D. Isoproterenol induced cardiac hypertrophy: A comparison of three doses and two delivery methods in C57BL/6J mice. PLoS One. 2024;19(7):e0307467. https://doi.org/10.1371/journal.pone.0307467.

Fujimura N, Sumita S, Narimatsu E, Nakayama Y, Shitinohe Y, Namiki A. Effects of isoproterenol on diaphragmatic contractility in septic peritonitis. Am J Respir Crit Care Med. 2000;161(2 Pt 1):440-446. https://doi.org/10.1164/ajrccm.161.2.9904044.

Rebrova TY, Korepanov VA, Stepanov I V, Afanasiev SA. Modeling of isoproterenol-induced chronic heart failure in 24-month-old rats. Bull Exp Biol Med. 2024;178(1):30-33. https://doi.org/10.1007/s10517-024-06277-8.

Nadu AP, Ferreira AJ, Reudelhuber TL, Bader M, Santos RA. Reduced isoproterenol-induced renin-angiotensin changes and extracellular matrix deposition in hearts of TGR(A1–7)3292 rats. J Am Soc Hypertens. 2008;2(5):341-348. https://doi.org/10.1016/j.jash.2008.04.012.

Grimm D, Elsner D, Schunkert H, Pfeifer M, Griese D, Bruckschlegel G. Development of heart failure following isoproterenol administration in the rat: Role of the renin–angiotensin system. Cardiovasc Res. 1998;37(1):91-100. https://doi.org/10.1016/S0008-6363(97)00212-5.

Keihanian F, Moohebati M, Saeidinia A, Mohajeri SA, Madaeni S. Therapeutic effects of medicinal plants on isoproterenol-induced heart failure in rats. Biomed Pharmacother. 2021;134:111101. https://doi.org/10.1016/j.biopha.2020.111101.

Driscoll DJ, Gillette PC, Lewis RM, Hartley CJ, Schwartz A. Comparative hemodynamic effects of isoproterenol, dopamine, and dobutamine in the newborn dog. Pediatr Res. 1979;13(9):1006-1009. https://doi.org/10.1203/00006450-197909000-00011.

Zinzuvadia D, Suthar J, Patel A, Shah U, Solanki N, Koria H. Gynostemma pentaphyllum Makino exerts cardioprotective effects by improving hemodynamic, biochemical and histopathological changes through activation of PI3K signalling in isoproterenol-induced myocardial infarction in rats. Am J Transl Res. 2024;16(6):2290-2300. https://doi.org/10.62347/GHIX8452.


Forte E, Panahi M, Baxan N, Ng FS, Boyle JJ, Branca J, et al. Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart. J Cell Mol Med. 2021;25(1):229-243. https://doi.org/10.1111/jcmm.15937.

Pan Y, Gao J, Gu R, Song W, Li H, Wang J, et al. Effect of injection of different doses of isoproterenol on the hearts of mice. BMC Cardiovasc Disord. 2022;22(1):409. https://doi.org/10.1186/s12872-022-02852-x.

Krenek P, Kmecova J, Kucerova D, Bajuszova Z, Musil P, Gazova A, et al. Isoproterenol-induced heart failure in the rat is associated with nitric oxide-dependent functional alterations of cardiac function. Eur J Heart Fail. 2009;11(2):140-146. https://doi.org/10.1093/eurjhf/hfn026.

Cano IP, Dionisio TJ, Cestari TM, Calvo AM, Colombini-Ishikiriama BL, Faria FAC, et al. Losartan and isoproterenol promote alterations in the local renin-angiotensin system of rat salivary glands. PLoS One. 2019;14(5): e0217030 https://doi.org/10.1371/journal.pone.0217030.

Kim JE, Kang YJ, Lee KY, Choi HC. Isoproterenol inhibits angiotensin IIstimulated proliferation and reactive oxygen species production in vascular smooth muscle cells through heme oxygenase-1. Biol Pharm Bull. 2009;32(6):1047-1052. https://doi.org/10.1248/bpb.32.1047.

Leenen FH, White R, Yuan B. Isoproterenol-induced cardiac hypertrophy: Role of circulatory versus cardiac renin-angiotensin system. Am J Physiol Heart Circ Physiol. 2001;281(6):H2410-6. https://doi.org/10.1152/ajpheart.2001.281.6.H2410.

Mohammadi SG, Feizi A, Bagherniya M, Shafie D, Ahmadi A-R, Kafeshani M. The effect of astaxanthin supplementation on inflammatory markers, oxidative stress indices, lipid profile, uric acid level, blood pressure, endothelial function, quality of life, and disease symptoms in heart failure subjects. Trials. 2024;25(1):518. https://doi.org/10.1186/s13063-024-08339-8.

Kato T, Kasai T, Sato A, Ishiwata S, Yatsu S, Matsumoto H, et al. Effects of 3-month astaxanthin supplementation on cardiac function in heart failure patients with left ventricular systolic dysfunction - A pilot study. Nutrients. 2020;12(6): 1896. https://doi.org/10.3390/nu12061896.

Sarker M, Chowdhury N, Bristy AT, Emran T, Karim R, Ahmed R, et al. Astaxanthin protects fludrocortisone acetate-induced cardiac injury by attenuating oxidative stress, fibrosis, and inflammation through TGF-β/Smad signaling pathway. Biomed Pharmacother. 2024;181:117703. https:// doi.org/10.1016/j.biopha.2024.117703.

Pereira CPM, Souza ACR, Vasconcelos AR, Prado PS, Name JJ. Antioxidant and anti‑inflammatory mechanisms of action of astaxanthin in cardiovascular diseases (Review). Int J Mol Med. 2021;47(1):37-48. https://doi.org/10.3892/ijmm.2020.4783.

Gao C, Gong N, Chen F, Hu S, Zhou Q, Gao X. The effects of astaxanthin on metabolic syndrome: A comprehensive review. Mar Drugs. 2025;23(1):9. https://doi.org/10.3390/md23010009.

Wang Y, Thatcher SE, Cassis LA. Measuring blood pressure using a noninvasive tail cuff method in mice. Methods Mol Biol. 2017;1614:69-73. https://doi.org/10.1007/978-1-4939-7030-8_6.

Stegemann H, Stalder K. Determination of hydroxyproline. Clin Chim Acta. 1967;18(2):267-273. https://doi.org/10.1016/0009-8981(67)90167-2.

Cissell DD, Link JM, Hu JC, Athanasiou KA. A modified hydroxyproline assay based on hydrochloric acid in Ehrlich’s solution accurately measures tissue collagen content. Tissue Eng Part C Methods. 2017;23(4):243-250. https://doi.org/10.1089/ten.tec.2017.0018.

Singh H, Kaur P, Kaur P, Muthuraman A, Singh G, Kaur M. Investigation of therapeutic potential and molecular mechanism of vitamin P and digoxin in I/R- induced myocardial infarction in rat. Naunyn Schmiedebergs Arch Pharmacol. 2015;388(5):565-574. https://doi.org/10.1007/s00210-015-1103-8.

Dewi S, Ramadhani ANA, Azzahra KA, Wardaya W. Specific activity of lactate dehydrogenase in muscle and liver tissues of rats exposed to intermittent hypobaric hypoxia. BIO Integration. 2025; 6: 1–6. https://doi.org/10.15212/bioi-2024-0074.

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-275. https://doi.org/10.1016/S0021-9258(19)52451-6.

Nikam AP, Ghule AE, Piplani P, Bansal J, Bodhankar SL. Cardioprotective and antiarrythmic activity of oxalate salt of 1-(isopropylamino)-3-(5- ((isopropylamino) methyl)-2-methoxyphenoxy) propan-2-ol (PP-24): A newly synthesized aryloxypropanolamine derivative. Biomed Aging Pathol. 2011;1(2):84-89. https://doi.org/10.1016/j.biomag.2011.06.003.

Bader Eddin L, Nagoor Meeran MF, Kumar Jha N, Goyal SN, Ojha S. Isoproterenol mechanisms in inducing myocardial fibrosis and its application as an experimental model for the evaluation of therapeutic potential of phytochemicals and pharmaceuticals. Animal Model Exp Med. 2025;8(1):67-91. https://doi.org/10.1002/ame2.12496.

Shakery A, Pourvali K, Shimi G, Zand H. Isoproterenol Alters Metabolism, Promotes Survival and Migration in 5-Fluorouracil-Treated SW480 Cells with and without Beta-hydroxybutyrate. Int J Mol Cell Med. 2023;12(2):144-158. https://doi.org/10.22088/IJMCM.BUMS.12.2.144.

Liu J, Li W, Jiao R, Liu Z, Zhang T, Chai D, et al. Miglustat ameliorates isoproterenol-induced cardiac fibrosis via targeting UGCG. Mol Med. 2025;31(1): 288. https://doi.org/10.1186/s10020-025-01360-w.

Busatto VC, Cunha V, Cicilini MA, Mill JG. Differential effects of isoproterenol on the activity of angiotensin-converting enzyme in the rat heart and aorta. Braz J Med Biol Res. 1999;32(3):355-360. https://doi.org/10.1590/s0100-879x1999000300017.

Leenen FH, McDonald RH Jr. Effect of isoproterenol on blood pressure, plasma renin activity, and water intake in rats. Eur J Pharmacol.1974;26(2):129-135. https://doi.org/10.1016/0014-2999(74)90218-0.

Chowdhury D, Tangutur AD, Khatua TN, Saxena P, Banerjee SK, Bhadra MP. A proteomic view of isoproterenol induced cardiac hypertrophy: Prohibitin identified as a potential biomarker in rats. J Transl Med. 2013;11:130. https://doi.org/10.1186/1479-5876-11-130.

Erokhina IL, Okovityĭ S V, Kulikov AN, Kazachenko AA, Emel’ianova OI. Effects of reninangiotensin system inhibitors on density of rat myocardial, pericardial, and pulmonary mast cells in experimental heart failure. Cell Tiss Biol. 2009;3:544-550. https://doi.org/10.1134/S1990519X09060078.

Szymanski MW, Singh DP. Isoproterenol. In: StatPearls [Internet]. Treasure Island (FL); StatPearls Publishing. 2025. Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK526042/

Gallego M, Espiña L, Vegas L, Echevarria E, Iriarte MM, Casis O. Spironolactone and captopril attenuates isoproterenol-induced cardiac remodelling in rats. Pharmacol Res. 2001;44(4):311-315. https://doi.org/10.1006/phrs.2001.0865.

Bin-Jaliah I, Hussein AM, Sakr HF, Eid EA. Effects of low dose of aliskiren on isoproterenol-induced acute myocardial infarction in rats. Physiol Int. 2018;105(2):127-144. https://doi.org/10.1556/2060.105.2018.2.11.

Weng LQ, Zhang WB, Ye Y, Yin PP, Yuan J, Wang XX, et al. Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice. Acta Pharmacol Sin. 2014;35(8):1005-1014. https://doi.org/10.1038/aps.2014.45.

Zhao Z, Liu H, Guo D. Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways. Braz J Med Biol Res. 2020;53(2):e8793. https://doi.org/10.1590/1414-431X20198793.

Keles MS, Bayir Y, Suleyman H, Halici Z. Investigation of effects of Lacidipine, Ramipril and Valsartan on DNA damage and oxidative stress occurred in acute and chronic periods following isoproterenol-induced myocardial infarct in rats. Mol Cell Biochem. 2009;328(1-2):109-117. https://doi.org/10.1007/s11010-009-0080-y.

Khloussy HM, Badawy AD, Mohamed YSIE, Maher M. Role of 17-β estradiol and ramipril in OPG/RANKL pathway in a rat model of post-menopausal osteoporosis. Egypt J Hosp Med. 2023;90(1):522-527. https://doi.org/10.21608/ejhm.2023.279677.

Mahmoud DSE, Kamel MA, El-Sayed IE, Binsuwaidan R, Elmongy EI, Razzaq MK, et al. Astaxanthin ameliorated isoproterenol induced myocardial infarction via improving the mitochondrial function and antioxidant activity in rats. J Biochem Mol Toxicol. 2024;38(8):e23804. https://doi.org/10.1002/jbt.23804.

Ni Y, Nagashimada M, Zhuge F, Zhan L, Nagata N, Tsutsui A, et al. Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E. Sci Rep. 2015;5:17192. https://doi.org/10.1038/srep17192.

Althammer F, Roy RK, Kirchner MK, Podpecan Y, Helen J, McGrath S, Campos Lira E, Stern JE. Angiotensin-II drives changes in microglia-vascular interactions in rats with heart failure. Commun Biol. 2024;7(1):1537. https://doi.org/10.1038/s42003-024-07229-8.

Guo BY, Li YJ, Han R, Yang SL, Shi YH, Han DR, et al. Telmisartan attenuates isoproterenol-induced cardiac remodeling in rats via regulation of cardiac adiponectin expression. Acta Pharmacol Sin. 2011;32(4):449-455. https://doi.org/10.1038/aps.2010.231.

Hussein G, Nakamura M, Zhao Q, Iguchi T, Goto H, Sankawa U, et al. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. Biol Pharm Bull. 2005;28(1):47-52. https://doi.org/10.1248/bpb.28.47.

Preuss HG, Echard B, Bagchi D, Perricone NV, Yamashita E. Astaxanthin lowers blood pressure and lessens the activity of the renin-angiotensin system in Zucker fatty rats. J Funct Foods. 2009;1(1):13-22. https://doi.org/10.1016/j.jff.2008.09.001.

Mokhtari E, Rafiei S, Shokri-Mashhadi N, Saneei P. Impact of astaxanthin supplementation on blood pressure: A systematic review and meta-analysis of randomized controlled trials. J Funct Foods. 2021;87:104860. https://doi.org/10.1016/j.jff.2021.104860.