Effect of Thrombin Fragment (TP508) on Myocardial Ischemia-reperfusion Injury in Hypercholesterolemic Pigs

Overview

Journal J Appl Physiol (1985)

Publisher American Physiological Society

Date 2009 Apr 18

PMID 19372304

Citations 10

Authors

Robert M Osipov

Michael P Robich

Jun Feng

Richard T Clements

Yuhong Liu

Hilary P Glazer

John Wagstaff

Cesario Bianchi

Frank W Sellke

Affiliations

Soon will be listed here.

Abstract

Myocardial ischemia-reperfusion (IR) injury occurs frequently in the setting of hypercholesterolemia. We investigated the potential efficacy of a novel thrombin fragment (TP508) on IR injury in a hypercholesterolemic porcine model. Twenty-one hypercholesterolemic male Yucatan pigs underwent 60 min of mid-left anterior descending coronary artery occlusion followed by 120 min of reperfusion. Pigs received either placebo (control, n = 7) or TP508 in two doses (TP508 low dose, n = 7, as bolus of 0.5 mg/kg 50 min into ischemia and an infusion of 1.25 mg.kg(-1).h(-1) during reperfusion period or TP508 high dose, n = 7, a double dose of TP508 low-dose group). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis were determined by Monastryl blue/triphenyl tetrazolium chloride staining. Apoptosis in the ischemic territory was assessed. Coronary microvascular reactivity to endothelium-dependent and -independent factors was measured. Myocardial necrosis was lower in both TP508-treated groups vs. control (P < 0.05). Regional left ventricular function was improved only in the TP508 high-dose group (P < 0.05). Endothelium-dependent coronary microvascular reactivity was greater in both TP508-treated groups (P < 0.05) vs. control. The expression of proteins favoring cell survival, 90-kDa heat shock protein and phospho-Bad (Ser112) was higher in the TP508 high-dose group (P < 0.05). The expression of the cell death signaling proteins, cleaved caspase-3 (P < 0.05), apoptosis-inducing factor (P < 0.05), and poly-ADP ribose polymerase (P = 0.07) was lower in the TP508 low-dose group vs. TP508 high-dose and control. The terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cell count was lower in both TP508 groups compared with the control (P < 0.05). This study demonstrates that, in hypercholesterolemic pigs, TP508 decreases myocardial necrosis and apoptosis after IR. Thus TP508 may offer a novel approach in protecting the myocardium from IR injury.

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References

Sodha N, Clements R, Feng J, Liu Y, Bianchi C, Horvath E . The effects of therapeutic sulfide on myocardial apoptosis in response to ischemia-reperfusion injury. Eur J Cardiothorac Surg. 2008; 33(5):906-13. PMC: 2424271. DOI: 10.1016/j.ejcts.2008.01.047. View

Norfleet A, Bergmann J, Carney D . Thrombin peptide, TP508, stimulates angiogenic responses in animal models of dermal wound healing, in chick chorioallantoic membranes, and in cultured human aortic and microvascular endothelial cells. Gen Pharmacol. 2002; 35(5):249-54. DOI: 10.1016/s0306-3623(01)00118-5. View

Beere H, Wolf B, Cain K, Mosser D, Mahboubi A, Kuwana T . Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol. 2000; 2(8):469-75. DOI: 10.1038/35019501. View

Cai H, Harrison D . Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87(10):840-4. DOI: 10.1161/01.res.87.10.840. View

Yu C, Jia L, Meng Y, Zhao J, Zhang Y, Qiu X . Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2. Gene Ther. 2005; 13(4):313-20. DOI: 10.1038/sj.gt.3302672. View

Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H, Kawamura S . Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. Cardiovasc Res. 2000; 45(3):642-50. DOI: 10.1016/s0008-6363(99)00271-0. View

Perrault L, Mahlberg F, Breugnot C, Bidouard J, Villeneuve N, Vilaine J . Hypercholesterolemia increases coronary endothelial dysfunction, lipid content, and accelerated atherosclerosis after heart transplantation. Arterioscler Thromb Vasc Biol. 2000; 20(3):728-36. DOI: 10.1161/01.atv.20.3.728. View

Lepore D, Knight K, Anderson R, Morrison W . Role of priming stresses and Hsp70 in protection from ischemia-reperfusion injury in cardiac and skeletal muscle. Cell Stress Chaperones. 2001; 6(2):93-6. PMC: 434395. DOI: 10.1379/1466-1268(2001)006<0093:ropsah>2.0.co;2. View

Zhong D, Liu X, Khuri F, Sun S, Vertino P, Zhou W . LKB1 is necessary for Akt-mediated phosphorylation of proapoptotic proteins. Cancer Res. 2008; 68(18):7270-7. PMC: 2596073. DOI: 10.1158/0008-5472.CAN-08-1484. View

10.

Tsopanoglou N, Papaconstantinou M, Flordellis C, Maragoudakis M . On the mode of action of thrombin-induced angiogenesis: thrombin peptide, TP508, mediates effects in endothelial cells via alphavbeta3 integrin. Thromb Haemost. 2004; 92(4):846-57. DOI: 10.1160/TH04-04-0208. View

11.

Bolli R, Becker L, Gross G, Mentzer Jr R, Balshaw D, Lathrop D . Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res. 2004; 95(2):125-34. DOI: 10.1161/01.RES.0000137171.97172.d7. View

12.

Toyoda Y, Di Gregorio V, Parker R, Levitsky S, McCully J . Anti-stunning and anti-infarct effects of adenosine-enhanced ischemic preconditioning. Circulation. 2000; 102(19 Suppl 3):III326-31. DOI: 10.1161/01.cir.102.suppl_3.iii-326. View

13.

Ohtsuka K, Hata M . Molecular chaperone function of mammalian Hsp70 and Hsp40--a review. Int J Hyperthermia. 2000; 16(3):231-45. DOI: 10.1080/026567300285259. View

14.

Quintana M, Kahan T, Hjemdahl P . Pharmacological prevention of reperfusion injury in acute myocardial infarction. A potential role for adenosine as a therapeutic agent. Am J Cardiovasc Drugs. 2004; 4(3):159-67. DOI: 10.2165/00129784-200404030-00003. View

15.

Fossum T, Olszewska-Pazdrak B, Mertens M, Makarski L, Miller M, Hein T . TP508 (Chrysalin) reverses endothelial dysfunction and increases perfusion and myocardial function in hearts with chronic ischemia. J Cardiovasc Pharmacol Ther. 2008; 13(3):214-25. DOI: 10.1177/1074248408321468. View

16.

Kloner R, Arimie R, Kay G, Cannom D, Matthews R, Bhandari A . Evidence for stunned myocardium in humans: a 2001 update. Coron Artery Dis. 2001; 12(5):349-56. DOI: 10.1097/00019501-200108000-00003. View

17.

Zhao J, Yang Y, You S, Cui C, Gao R . Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc Res. 2006; 73(2):137-42. DOI: 10.1016/j.mvr.2006.09.002. View

18.

Zakeri Z, Lockshin R . Cell death: history and future. Adv Exp Med Biol. 2008; 615:1-11. DOI: 10.1007/978-1-4020-6554-5_1. View

19.

Spurlock M, Gabler N . The development of porcine models of obesity and the metabolic syndrome. J Nutr. 2008; 138(2):397-402. DOI: 10.1093/jn/138.2.397. View

20.

Guzman M, Crisostomo P, Wang M, Markel T, Wang Y, Meldrum D . Vascular endothelial growth factor improves myocardial functional recovery following ischemia/reperfusion injury. J Surg Res. 2008; 150(2):286-92. DOI: 10.1016/j.jss.2007.12.772. View