Abstract
Aim:
To determine the cardioprotective action of ghrelin and des-octanoyl ghrelin in rats with isoproterenol-induced myocardial injury.
Methods:
Rats were subcutaneously injected with isoproterenol (ISO; 20, 10, and 5 mg/kg) on d 1, 2 and 3, respectively, and then 3 mg/kg for the next 7 d with or without ghrelin or des-octanoyl-ghrelin (100 μg/kg, twice daily). Plasma ghrelin and growth hormone levels were assayed using radioimmunoassay methods. Growth hormone secretagogue receptor (GHSR) and ghrelin mRNA were determined using RT-PCR. The maximal binding capacity and the affinity for [3H] ghrelin were determined by receptor binding assays.
Results:
Compared with controls, ISO-treated rats showed severe myocardial injury, cardiomegaly, infarction-like necrosis and massive fibrosis with increases in irradiated-ghrelin (ir-ghrelin) content in plasma by 67% and myocardia by 66% and in the mRNA level in the myocardia by 93% (P<0.01). ISO-treated rats had 95% (P<0.01) higher GHSR mRNA levels in the myocardia. The maximal binding capacity of [3H]ghrelin for myocardial sarcolemma was higher in ISO-treated rats than in controls. Ghrelin administration improved cardiac function and ameliorated cardiomegaly and attenuated myocardial lipid peroxidation injury and relieved cardiac fibrosis as compared with ISO treatment alone. Administration of des-octanoyl ghrelin effectively antagonized ISO-induced myocardial injury and improved all parameters measured. However, the therapeutic effect of des-octanoyl ghrelin was significantly weaker than that of ghrelin. The plasma growth hormone level increased markedly, by 1.5-fold (P<0.01), with ghrelin administration as compared with that in controls, but was unaltered in the des-octanoyl ghrelin group.
Conclusion:
Myocardial ghrelin and GHSR were up-regulated during ISO-induced myocardial injury. The protective effect of ghrelin against ISO-induced cardiac function injury and fibrosis was more potent than that of des-octanoyl ghrelin, which suggests that ghrelin could be an endogenous cardioprotective factor in ischemic heart disease, and that its effects include growth hormone-dependent and -independent pathways.
Similar content being viewed by others
Article PDF
References
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K . Ghrelin is a growth hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–60.
St-Pierre DH, Wang L, Tache Y . Ghrelin: a novel player in the gut-brain regulation of growth hormone and energy balance. News Physiol Sci 2003; 18: 242–6.
Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002; 87: 240–4.
Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988–91.
Papotti M, Ghe C, Cassoni P, Catapano F, Deghenghi R, Ghigo E, et al. Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab 2000; 85: 3803–7.
Jeffery PL, Herington AC, Chopin LK . The potential autocrine/paracrine roles of ghrelin and its receptor in hormone-dependent cancer. Cytokine Growth Factor Rev 2003; 14: 113–22.
Chang L, Ren Y, Liu X, Li WG, Yang J, Geng B, et al. Protective effects of ghrelin on ischemia/reperfusion injury in the isolated rat heart. J Cardiovasc Pharmacol 2004; 43: 165–70.
Chang L, Du JB, Gao LR, Pang YZ, Tang CS . Effect of ghrelin on septic shock in rats. Acta Pharmacol Sin 2003; 24: 45–9.
Chang L, Zhao J, Li GZ, Geng B, Pan CS, Qi YF, et al. Ghrelin protects myocardium from isoproterenol-induced injury in rats. Acta Pharmacol Sin 2004; 25: 113–7.
Tschop M, Smiley DL, Heiman ML . Ghrelin induces adiposity in rodents. Nature 2000; 407: 908–13.
Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, et al. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004; 145: 234–42.
Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghe C, et al. Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin. Eur J Pharmacol 2003; 476: 87–95.
Rona G, Chappel CI, Balzas T, Gaudry R . An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. Arch Pathol 1959; 67: 443–55.
Ohkawa H, Ohishi N, Yagi K . Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351–8.
Corongiu F, Banni S, Dessi M . Conjugated dienes detected in tissue lipid extracts by second derivative spectrophotometry. Free Radic Biol Med 1989; 7: 183–6.
Young M, Fullerton M, Dilley R, Funder J . Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest 1994; 93: 2578–83.
Qi YF, Bu DF, Niu DD, Shi YR, Wang SH, Pang YZ, et al. Effects of different peptide fragments derived from proadrenomedullin on gene expression of adrenomedullin gene. Peptides 2002; 23: 114–7.
Wol AA, Hines DK, Karliner JS . Refined membrane preparations mask ischemic fall in myocardial beta receptor density. Am J Physiol 1989; 257: H1032–6.
Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–54.
Tang CS, Liu MS . Initial externalization followed by internalization of adrenergic receptors in rat heart during sepsis. Am J Physiol 1996; 270: R254–63.
Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M . Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 2002; 40: 694–9.
Shimizu Y, Nagaya N, Teranishi Y, Imazu M, Yamamoto H, Shokawa T, et al. Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun 2003; 310: 830–5.
Wiley KE, Davenport AP . Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol 2002; 136: 1146–52.
Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, et al. Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci 2003; 105: 431–5.
Nagaya N, Miyatake K, Uematsu M, Oya H, Shimizu W, Hosoda H, et al. Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab 2001; 86: 5854–9.
Kishimoto M, Okimura Y, Nakata H, Kudo T, Iguchi G, Takahashi Y, et al. Cloning and characterization of the 5(V)-flanking region of the human ghrelin gene. Biochem Biophys Res Commun 2003; 305: 186–92.
Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 2004; 109: 2221–6.
Volterrani M, Giustina A, Lorusso R, Giordano A . Does growth hormone play a role in chronic heart failure? Heart Fail Monit 2002; 3: 60–4.
Ryoke T, Gu Y, Mao L, Hongo M, Clark RG, Peterson KL, et al. Progressive cardiac dysfunction and fibrosis in the cardiomyopathic hamster and effects of growth hormone and angiotensin-converting enzyme inhibition. Circulation 1999; 100: 1734–43.
Imanishi R, Ashizawa N, Ohtsuru A, Seto S, Akiyama-Uchida Y, Kawano H, et al. GH suppresses TGF-beta-mediated fibrosis and retains cardiac diastolic function. Mol Cell Endocrinol 2004; 218: 137–46.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the Major State Basic Research Development Program of the People's Republic of China (No G2000-056905) and the National Natural Science Foundation of China (No 30470693).
Rights and permissions
About this article
Cite this article
Li, L., Zhang, Lk., Pang, Yz. et al. Cardioprotective effects of ghrelin and des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats. Acta Pharmacol Sin 27, 527–535 (2006). https://doi.org/10.1111/j.1745-7254.2006.00319.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2006.00319.x
Keywords
This article is cited by
-
Heal the heart through gut (hormone) ghrelin: a potential player to combat heart failure
Heart Failure Reviews (2021)
-
Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
Scientific Reports (2020)
-
β-Adrenoreceptor Agonist Isoproterenol Alters Oxidative Status, Inflammatory Signaling, Injury Markers and Apoptotic Cell Death in Myocardium of Rats
Indian Journal of Clinical Biochemistry (2015)
-
Protective effects of desacyl ghrelin on diabetic cardiomyopathy
Acta Diabetologica (2015)
-
Lagerstroemia speciosa L. Attenuates Apoptosis in Isoproterenol-Induced Cardiotoxic Mice by Inhibiting Oxidative Stress: Possible Role of Nrf2/HO-1
Cardiovascular Toxicology (2015)