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
References
- 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.
https://doi.org/10.1016/S0022-5223(96)70068-5 - 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.
https://doi.org/10.1111/j.1365-2362.2000.00712.x - Verma S, Fedak PW, Weisel RD, et al. Off-pump coronary artery bypass surgery: fundamentals for the clinical cardiologist. Circulation 2004;109:1206-1211.
https://doi.org/10.1161/01.CIR.0000120292.65143.F5 - 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.
https://doi.org/10.1038/nm1198 - Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia–reperfusion injury. Cardiovasc Res 1999;43: 860–878.
https://doi.org/10.1016/S0008-6363(99)00187-X - 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.
https://doi.org/10.1016/j.ejcts.2005.07.007 - 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.
https://doi.org/10.1097/00024382-200116001-00007 - Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. Eur J Cardiothorac Surg 2002;21:232-244.
https://doi.org/10.1016/S1010-7940(01)01099-5 - 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.
https://doi.org/10.1097/FJC.0b013e31802c0cd0 - 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.
https://doi.org/10.1126/science.273.5277.974 - Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–60. [PubMed]
https://doi.org/10.1038/45230 - 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.
https://doi.org/10.1096/fj.03-0641rev - van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocrine Rev 2004;25:426–57.
https://doi.org/10.1210/er.2002-0029 - Hosoda H, Kojima M, Kangawa K. Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 2006;100:398–410. [PubMed]
https://doi.org/10.1254/jphs.CRJ06002X - 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.
https://doi.org/10.1111/j.1365-2265.2004.01944.x - 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.
https://doi.org/10.1152/ajpheart.00193.2004 - 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.
https://doi.org/10.1016/j.tox.2008.02.018 - 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.
https://doi.org/10.1002/micr.20363 - 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.
https://doi.org/10.1172/JCI116922 - Nagaya N, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failure. Regul. Pept 2003;114:71–77.
https://doi.org/10.1016/S0167-0115(03)00117-4 - Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000;407:908–913.
https://doi.org/10.1038/35038090 - 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.
https://doi.org/10.1161/hc3601.095575 - 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.
https://doi.org/10.1097/00005344-200402000-00001 - Locatelli V, Rjossoni G, Schweiger F, et al. Growth hormone-independent cardioprotective effects of hexarelin in the rat. Endocrinology 1999;140:4024-4031.
https://doi.org/10.1210/endo.140.9.6948 - 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.
https://doi.org/10.1210/jcem.87.6.8739 - 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.
https://doi.org/10.1097/01.sla.0000251614.42290.ed - 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.
https://doi.org/10.1210/jcem.86.12.8115
Research Article
DOI: http://dx.doi.org/10.18081/ajbm/2333-5106-013-12/38-48
American Journal of BioMedicine Volume 2, Issue 1, pages 37-47
Received September 21, 2013; accepted November 20, 2013; published February 11, 2014