Ghrelin、obestatin在冠心病及其危险因素中的作用及机制研究
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摘要
目的:探讨ghrelin和obestatin在冠心病及其危险因素肥胖症中的水平变化及其作用,并初步探讨其中机制。
方法:采用放射免疫法检测肥胖症和冠心病患者外周血ghrelin、obestatin水平;观察obestatin对3T3-L1前脂肪细胞增殖和分化的影响;并采用Langendorff离体大鼠心脏灌流模型及缺血再灌注损伤模型,观察obestatin对正常离体心脏及缺血再灌注损伤的作用;以及obestatin对H5V血管内皮细胞增殖和细胞黏附分子表达的影响。
结果:肥胖症患者餐前外周血obestatin相对水平明显降低。Obestatin可以明显抑制3T3-L1前脂肪细胞的增殖和分化。冠心病患者外周血obestatin的绝对和相对水平均明显升高。Obestatin可以通过Rho激酶及PI3-K途径加重离体心脏的缺血再灌注损伤。Obestatin可以明显抑制血管内皮细胞增殖,增加ICAM-1、VCAM-1表达,其中部分机制是通过Rho激酶及PI3-K途径。
结论:冠心病和肥胖症患者外周血均存在ghrelin/obestatin水平失衡。Obestatin可能是一个新的冠心病危险因子。
Objective: To investigate changes of circulating ghrelin and obestatin levels, their roles and mechanisms in coronary artery disease (CAD) and obesity.
Methods: Plasma total ghrelin and obestatin levels were measured by RIA in CAD and obesity patients. Effect of obestatin on proliferation and differentiation of 3T3-L1 preadipocytes was investigated. Effects of obestatin on isolated rat hearts was investigated in normal and ischemia/reperfusion Langendorff models. Effect of obestatin on proliferation and expression of cell adhesion molecules of H5V endothelial cells was also investigated.
Results: Circulating preprandial ghrelin to obestatin ratio was elevated in human obesity. Obestatin inhibited the proliferation and differentiation of 3T3-L1 preadipocytes. Both absolute and relative obestatin levels were increased in CAD patients. Obestatin could deteriorate cardiac function damage induced by ischemia and reperfusion in the Langendorf model of rat heart through the Rho kinase and PI3-K pathways. Obestatin inhibited the proliferation of endothelial cells through the Rho kinase and PI3-K pathways, and increased adhesion molecules expression.
Conclusion: There is imbalance of circulating ghrelin and obestatin levels both in CAD and obesity patients, and obestatin may be a new risk factor of CAD.
方法:采用放射免疫法检测肥胖症和冠心病患者外周血ghrelin、obestatin水平;观察obestatin对3T3-L1前脂肪细胞增殖和分化的影响;并采用Langendorff离体大鼠心脏灌流模型及缺血再灌注损伤模型,观察obestatin对正常离体心脏及缺血再灌注损伤的作用;以及obestatin对H5V血管内皮细胞增殖和细胞黏附分子表达的影响。
结果:肥胖症患者餐前外周血obestatin相对水平明显降低。Obestatin可以明显抑制3T3-L1前脂肪细胞的增殖和分化。冠心病患者外周血obestatin的绝对和相对水平均明显升高。Obestatin可以通过Rho激酶及PI3-K途径加重离体心脏的缺血再灌注损伤。Obestatin可以明显抑制血管内皮细胞增殖,增加ICAM-1、VCAM-1表达,其中部分机制是通过Rho激酶及PI3-K途径。
结论:冠心病和肥胖症患者外周血均存在ghrelin/obestatin水平失衡。Obestatin可能是一个新的冠心病危险因子。
Objective: To investigate changes of circulating ghrelin and obestatin levels, their roles and mechanisms in coronary artery disease (CAD) and obesity.
Methods: Plasma total ghrelin and obestatin levels were measured by RIA in CAD and obesity patients. Effect of obestatin on proliferation and differentiation of 3T3-L1 preadipocytes was investigated. Effects of obestatin on isolated rat hearts was investigated in normal and ischemia/reperfusion Langendorff models. Effect of obestatin on proliferation and expression of cell adhesion molecules of H5V endothelial cells was also investigated.
Results: Circulating preprandial ghrelin to obestatin ratio was elevated in human obesity. Obestatin inhibited the proliferation and differentiation of 3T3-L1 preadipocytes. Both absolute and relative obestatin levels were increased in CAD patients. Obestatin could deteriorate cardiac function damage induced by ischemia and reperfusion in the Langendorf model of rat heart through the Rho kinase and PI3-K pathways. Obestatin inhibited the proliferation of endothelial cells through the Rho kinase and PI3-K pathways, and increased adhesion molecules expression.
Conclusion: There is imbalance of circulating ghrelin and obestatin levels both in CAD and obesity patients, and obestatin may be a new risk factor of CAD.
引文
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1 Tschop M, Smiley DL, Heiman ML, et al. Ghrelin induces adiposity in rodents. Nature, 2000, 407(6806): 908-913.
2 Wren AM, Small CJ, Abbott CR, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes, 2001, 50(11): 2540-2547.
3 Kim MS, Yoon CY, Jang PG, et al. The mitogenic and antiapoptotic actions of ghrelin in 3T3-L1 adipocytes. Mol Endocrinol, 2004, 18(9): 2291-2301.
4 Choi K, Roh SG, Hong YH, et al. The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis. Endocrinology, 2003, 144(3): 754-759.
5 Patel AD, Stanley SA, Murphy KG, et al. Ghrelin stimulates insulin-induced glucose uptake in adipocytes. Regul Pept, 2006, 134(1): 17-22.
6 Muccioli G, Pons N, Ghe C, et al. Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur J Pharmacol, 2004, 498(1-3): 27-35.
7 Theander-Carrillo C, Wiedmer P, Cettour-Rose P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest, 2006, 116(7): 1983-1993.
8 Zhang JV, Ren PG, Avsian-Kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science, 2005, 310(5750): 996-999.
9 Guo ZF, Zheng X, Qin YW, et al. Circulating preprandial ghrelin to obestatin ratio is increased in human obesity. J Clin Endocrinol Metab, 2007, 92(5): 1875-1880.
10 Szentirmai E, Krueger JM. Obestatin alters sleep in rats. Neurosci Lett, 2006, 404(1-2): 222-226.
11 Catalan V, Gomez-Ambrosi J, Rotellar F, et al. The obestatin receptor (GPR39) is expressed in human adipose tissue and is down-regulated in obesity-associated type 2 diabetes mellitus. Clin Endocrinol (Oxf), 2007, 66(4): 598-601.
12 12 Wu Z, Bucher NL, Farmer SR. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol Cell Biol, 1996, 16(8): 4128-4136.
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15 Moechars D, Depoortere I, Moreaux B, et al. Altered gastrointestinal and metabolic function in the GPR39-obestatin receptor-knockout mouse. Gastroenterology, 2006, 131(4): 1131-1141.
16 Camina JP, Campos JF, Caminos JE, et al. Obestatin-mediated proliferation of human retinal pigment epithelial cells: regulatory mechanisms. J Cell Physiol, 2007, 211(1): 1-9.
17 Holst B, Egerod KL, Schild E, et al. GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology, 2007, 148(1): 13-20.
18 Nogueiras R, Pfluger P, Tovar S, et al. Effects of obestatin on energy balance and growth hormone secretion in rodents. Endocrinology, 2007, 148(1): 21-26.
19 Seoane LM, Al-Massadi O, Pazos Y, et al. Central obestatin administration does not modify either spontaneous or ghrelin-induced food intake in rats. J Endocrinol Invest, 2006, 29(8): 13-15.
20 Bassil AK, Haglund Y, Brown J, et al. Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract. Br J Pharmacol, 2007, 150(1): 58-64.
21 de SB, Thijs T, Peeters TL, et al. Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents. Neurogastroenterol Motil, 2007, 19(3): 211-217.
22 Chartrel N, Alvear-Perez R, Leprince J, et al. Comment on "Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake". Science,2007, 315(5813): 766; author reply 766.
23 Sibilia V, Bresciani E, Lattuada N, et al. Intracerebroventricular acute and chronic administration of obestatin minimally affect food intake but not weight gain in the rat. J Endocrinol Invest, 2006, 29(11): 31-34.
24 Tremblay F, Perreault M, Klaman LD, et al. Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39. Endocrinology, 2007, 148(2): 501-506.
25 Lauwers E, Landuyt B, Arckens L, et al. Obestatin does not activate orphan G protein-coupled receptor GPR39. Biochem Biophys Res Commun, 2006, 351(1): 21-25.
26 Green BD, Irwin N, Flatt PR, et al. Direct and indirect effects of obestatin peptides on food intake and the regulation of glucose homeostasis and insulin secretion in mice. Peptides, 2007 (in press)
27 Zizzari P, Longchamps R, Epelbaum J, et al. Obestatin Partially Affects Ghrelin Stimulation of Food Intake and Growth Hormone Secretion in Rodents. Endocrinology, 2007, 148(4): 1648-1653.
28 Bresciani E, Rapetti D, Dona F, et al. Obestatin inhibits feeding but does not modulate GH and corticosterone secretion in the rat. J Endocrinol Invest, 2006, 29(8): 16-18.
29 Lagaud GJ, Young A, Acena A, et al. Obestatin reduces food intake and suppresses body weight gain in rodents. Biochem Biophys Res Commun, 2007 (in press)
1 Benso A, Broglio F, Marafetti L, et al. Ghrelin and synthetic growth hormone secretagogues are cardioactive molecules with identities and differences. Semin Vasc Med, 2004, 4(2): 107-114.
2 Sharma V, McNeill JH. The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology. Curr Vasc Pharmacol, 2005, 3(2): 169-180.
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5 Shimizu Y, Nagaya N, Teranishi Y, et al. Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun, 2003, 310(3): 830-835.
6 Tesauro M, Schinzari F, Iantorno M, et al. Ghrelin improves endothelial function inpatients with metabolic syndrome. Circulation, 2005, 112(19): 2986-2992.
7 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(8): 1146-1152.
8 Kleinz MJ, Maguire JJ, Skepper JN, et al. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res, 2006, 69(1): 227-235.
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