Everett W. Austin, Nasser Ghaly Yousif, Lihua Ao, Joseph C. Cleveland, David A. Fullerton, Xianzhong Meng¹*
Ghrelin is a small endogenous peptide principally produced and secreted by the gastric mucosa, with a major role in appetite and metabolism regulation. We hypothesized that anti-inflammatory therapy, as produced by exogenous administration of ghrelin, would decrease the myocardial inflammatory response to global hypothermia I/R, thereby affording myocardial protection. Heterotopic cervical heart transplantation that allows to subject donor hearts to global hypothermic ischemia and blood reperfusion, which very closely stimulates I/R conditions associated with cardiac surgical operations. Ghrelin administration prior to blood reperfusion significantly decreased serum concentrations of cTn-I versus animals subjected I/R alone, with a significantly attenuated VCAM-1 expression in I/R animals pre-treated with ghrelin. The tissue concentrations of pro-inflammatory cytokines (IL-6, IL-1β, and MCP-1) were ameliorated by the administration of ghrelin prior to reperfusion versus the concentrations observed in animals subjected to I/R alone. Significantly fewer monocytes in the tissue sections of I/R+ghrelin animals versus those subjected to I/R alone. Exogenous ghrelin administration prior to reperfusion of an ischemic heart resulted in a significant reduction in myocardial injury as measured by cTn-I. The reduced myocardial injury was accompanied by an attenuated tissue expression of several pro-inflammatory mediators, including VCAM-1, IL-6, IL-1β, and MCP-1.
Key Words: Global ischemia/reperfusion; Ghrelin; cTn-I; Pro-inflammatory cytokines; VCAM-1
- Wan S, DeSmet JM, Barvais L, Golstein M, Vincent JL, LeClerc JL. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;112: 806–811.
- Eberhardt F, Mehlhorn U, Larose K, DeVivie ER, Dhein S. Structural myocardial changes after coronary artery surgery. Eur J Clin Invest 2000;30: 938-946.
- Verma S, Fedak PW, Weisel RD, et al. Off-pump coronary artery bypass surgery: fundamentals for the clinical cardiologist. Circulation 2004;109:1206-1211.
- Petzelbauer P, Zacharowski PA, Miyazaki Y, et al. The fibrin-derived peptide B beta15–42 protects the myocardium against ischemia–reperfusion injury. Nat Med 2005;11:298-304.
- Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia–reperfusion injury. Cardiovasc Res 1999;43: 860–878.
- Franke A, Lante W, Fackeldey V, et al. Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: is what we see what we know. Eur J Cardiothorac Surg 2005;28:569-575.
- Harig F, Hohenstein B, von der Emde J, Weyand M. Modulating IL-6 and IL-10 levels by pharmacologic strategies and the impact of different extracorporeal circulation parameters during cardiac surgery. Shock 2001;16 Suppl 1:33-38.
- Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. Eur J Cardiothorac Surg 2002;21:232-244.
- Goudeau JJ, Clermont G, Guillery O, et al. In high-risk patients, combination of anti-inflammatory procedures during cardiopulmonary bypass can reduce incidences of inflammation and oxidative stress. J Cardiovasc Pharmacol 2007;49:39-45.
- Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996;273(5277):974–7.
- Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–60. [PubMed]
- Inui A, Asakawa A, Bowers CY, et al. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J 2004;18(3):439–56.
- van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocrine Rev 2004;25:426–57.
- Hosoda H, Kojima M, Kangawa K. Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 2006;100:398–410. [PubMed]
- Tritos NA, Kissinger KV, Manning WJ, Danias PG. Association between ghrelin and cardiovascular indexes in healthy obese and lean men. Clin Endocrinol (Oxf) 2004;60:60–6.
- Pemberton CJ, Tokola H, Bagi Z, et al. Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion. Am J Physiol Heart Circ Physiol 2004;287:H1522–9.
- Xu Z, Lin S, Wu W, et al. Ghrelin prevents doxorubicin-induced cardiotoxicity through TNF-alpha/NF-kappaB pathways and mitochondrial protective mechanisms. Toxicology 2008;247:133–8.
- Feng JE, Sun ZQ. A mouse cervical heart transplantation model using a cuff technique. Chin J Exp Surg 2005;22:1576-1577.
- Xiaodong Gu, Jianbin Xiang. Improved cuff technique for cervical heart transplantation in mice. Microsurgery 2007;27:317-319.
- Pinsky D, Oz M, Liao H, et al. Restoration of the camp 2nd messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model. J Clin Invest 1993;92: 2994.
- Nagaya N, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failure. Regul. Pept 2003;114:71–77.
- Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000;407:908–913.
- Chang L, Du JB, Gao LR, et al. Effect of ghrelin on septic shock in rats. Acta Pharmacol Sin 2003;24:45–49.
- Nagaya N, Uematsu M, Kojima M, et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 2001;104:1430–1435.
- Chang L, Ren Y, Liu X, Li WG, Yang J, Geng B, Weintraub NL, Tang C. Protective effects of ghrelin on ischemia/reperfusion injury in the isolated rat heart. J Cardiovasc Pharmacol 2004;43(2):165-70.
- Locatelli V, Rjossoni G, Schweiger F, et al. Growth hormone-independent cardioprotective effects of hexarelin in the rat. Endocrinology 1999;140:4024-4031.
- Gnanapavan S, Kola B, Bustin SA, 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.
- Wu R, Dong W, Cui X, et al. Ghrelin Down-regulates Proinflammatory Cytokines in Sepsis Through Activation of the Vagus Nerve. Annals of Surgery 2007;245(3):480-486.
- Nagaya N, Miyatake K, Uematsu M, et al. Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J. Clin. Endocrinol. Metab 2001;86:5854–5859.
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American Journal of BioMedicine Volume 2, Issue 1, pages 37-47
Received September 21, 2013; accepted November 20, 2013; published February 11, 2014
How to cite this article
Austin EW, Yousif NG, Ao L, Cleveland JC, Fullerton DA, Meng X. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. American Journal of BioMedicine 2014;2(1):26-36.
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