Activated protein C: A potential cardioprotective factor against ischemic injury during ischemia/reperfusion

American Journal of Translational Research

Volumn 1, Issue 4, 2009, Pages 381-392

  Wang, Jingying ^a   Li, Ji ^a  

^a UNIVERSITY AT BUFFALO   (United States)

Author keywords

Activated protein C (APC); AMP activated protein kinase (AMPK) pathway; Anti apoptosis; Anti inflammation; ERK MAPK pathway; Myocardial ischemia; PI3K Akt pathway

Indexed keywords

ACTIVATED PROTEIN C; APOPTOSIS INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B;

ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; CEREBROVASCULAR ACCIDENT; CYTOKINE RELEASE; DRUG MECHANISM; DRUG SCREENING; ENZYME ACTIVATION; HEART MUSCLE ISCHEMIA; HEART MUSCLE NECROSIS; HEART MUSCLE REPERFUSION; HEART PROTECTION; HUMAN; INFLAMMATION; NONHUMAN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REPERFUSION INJURY; RETINA INJURY; REVIEW; SPINAL CORD INJURY;

EID: 77953423996     PISSN: None     EISSN: 19438141     Source Type: Journal    
DOI: None     Document Type: Review

References (107)

1. Ferdinandy P, Schulz R and Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev 2007; 59: 418-458.
2. Fliss H and Gattinger D. Apoptosis in ischemic and reperfused rat myocardium. Circ Res 1996; 79: 949-956.
3. Chakrabarti S, Hoque AN and Karmazyn M. A rapid ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide). J Mol Cell Cardiol 1997; 29: 3169-3174.
4. Maulik N, Yoshida T and Das DK. Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase. Mol Cell Biochem 1999; 196: 13-21.
5. McCully JD, Wakiyama H, Hsieh YJ, Jones M and Levitsky S. Differential contribution of necrosis and apoptosis in myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2004; 286: H1923-1935.
6. Diaz RJ and Wilson GJ. Modifying the first minute of reperfusion: potential for myocardial salvage. Cardiovasc Res 2004; 62: 4-6.
7. Menshikova EV and Salama G. Cardiac ischemia oxidizes regulatory thiols on ryanodine receptors: captopril acts as a reducing agent to improve Ca2+ uptake by ischemic sarcoplasmic reticulum. J Cardiovasc Pharmacol 2000; 36: 656-668.
8. Fuller W, Parmar V, Eaton P, Bell JR and Shattock MJ. Cardiac ischemia causes inhibition of the Na/K ATPase by a labile cytosolic compound whose production is linked to oxidant stress. Cardiovasc Res 2003; 57: 1044-1051.
9. Zhu LP, Yu XD, Ling S, Brown RA and Kuo TH. Mitochondrial Ca(2+)homeostasis in the regulation of apoptotic and necrotic cell deaths. Cell Calcium 2000; 28: 107-117.
10. Schulz R. TNFalpha in myocardial ischemia/reperfusion: Damage vs. protection. J Mol Cell Cardiol 2008; 45: 712-714.
11. Neumann FJ, Ott I, Gawaz M, Richardt G, Holzapfel H, Jochum M and Schomig A. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 1995; 92: 748-755.
12. Bae JS, Yang L, Manithody C and Rezaie AR. The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 2007; 110: 3909-3916.
13. Wang M, Baker L, Tsai BM, Meldrum KK and Meldrum DR. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 2005; 288: E321-326.
14. Koskenkari JK, Rimpilainen J, Ohman H, Surcel HM, Vainionpaa V, Biancari F, Ala-Kokko T and Juvonen T. Leukocyte filter enhances neutrophil activation during combined aortic valve and coronary artery bypass surgery. Heart Surg Forum 2006; 9: E693-699.
15. Sharma HS and Das DK. Role of cytokines in myocardial ischemia and reperfusion. Mediators Inflamm 1997; 6: 175-183.
16. Hawkins HK, Entman ML, Zhu JY, Youker KA, Berens K, Dore M and Smith CW. Acute inflammatory reaction after myocardial ischemic injury and reperfusion. Development and use of a neutrophil-specific antibody. Am J Pathol 1996; 148: 1957-1969.
17. Wachtfogel YT, Kucich U, Greenplate J, Gluszko P, Abrams W, Weinbaum G, Wenger RK, Rucinski B, Niewiarowski S, Edmunds LH, Jr. and et al. Human neutrophil degranulation during extracorporeal circulation. Blood 1987; 69: 324-330.
18. Mitsos SE, Askew TE, Fantone JC, Kunkel SL, Abrams GD, Schork A and Lucchesi BR. Protective effects of N-2-mercaptopropionyl glycine against myocardial reperfusion injury after neutrophil depletion in the dog: evidence for the role of intracellular-derived free radicals. Circulation 1986; 73: 1077-1086.
19. Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA and Lucchesi BR. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 1983; 67: 1016-1023.
20. Yu CM, Lai KW, Chen YX, Huang XR and Lan HY. Expression of macrophage migration inhibitory factor in acute ischemic myocardial injury. J Histochem Cytochem 2003; 51: 625-631.
21. Miller EJ, Li J, Leng L, McDonald C, Atsumi T, Bucala R and Young LH. Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 2008; 451: 578-582.
22. Young LH, Li J, Baron SJ and Russell RR. AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends Cardiovasc Med 2005; 15: 110-118.
23. Zou MH, Hou XY, Shi CM, Kirkpatick S, Liu F, Goldman MH and Cohen RA. Activation of 5′-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxia-reoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J Biol Chem 2003; 278: 34003-34010.
24. Russell RR, 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ and Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 2004; 114: 495-503.
25. Coven DL, Hu X, Cong L, Bergeron R, Shulman GI, Hardie DG and Young LH. Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab 2003; 285: E629-636.
26. Kudo N, Gillespie JG, Kung L, Witters LA, Schulz R, Clanachan AS and Lopaschuk GD. Characterization of 5′AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta 1996; 1301: 67-75.
27. Li J, Hu X, Selvakumar P, Russell RR, 3rd, Cushman SW, Holman GD and Young LH. Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. Am J Physiol Endocrinol Metab 2004; 287: E834-841.
28. Russell RR, 3rd, Bergeron R, Shulman GI and Young LH. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol 1999; 277: H643-649.
29. Jorgensen SB, Nielsen JN, Birk JB, Olsen GS, Viollet B, Andreelli F, Schjerling P, Vaulont S, Hardie DG, Hansen BF, Richter EA and Wojtaszewski JF. The alpha2-5'AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. Diabetes 2004; 53: 3074-3081.
30. Hardie DG and Carling D. The AMP-activated protein kinase--fuel gauge of the mammalian cell? Eur J Biochem 1997; 246: 259-273.
31. Witczak CA, Sharoff CG and Goodyear LJ. AMP-activated protein kinase in skeletal muscle: from structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci 2008; 65: 3737-3755.
32. Li J, Coven DL, Miller EJ, Hu X, Young ME, Carling D, Sinusas AJ and Young LH. Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart. Am J Physiol Heart Circ Physiol 2006; 291: H1927-1934.
33. Polekhina G, Gupta A, van Denderen BJ, Feil SC, Kemp BE, Stapleton D and Parker MW. Structural basis for glycogen recognition by AMP-activated protein kinase. Structure 2005; 13: 1453-1462.
34. Birk JB and Wojtaszewski JF. Predominant alpha2/beta2/gamma3 AMPK activation during exercise in human skeletal muscle. J Physiol 2006; 577: 1021-1032.
35. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR and Hardie DG. Complexes between the LKB1 tumor suppressor, STRAD alpha/ beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003; 2: 28.
36. Sakamoto K, McCarthy A, Smith D, Green KA, Grahame Hardie D, Ashworth A and Alessi DR. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. Embo J 2005; 24: 1810-1820.
37. Sakamoto K, Zarrinpashneh E, Budas GR, Pouleur AC, Dutta A, Prescott AR, Vanoverschelde JL, Ashworth A, Jovanovic A, Alessi DR and Bertrand L. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1. Am J Physiol Endocrinol Metab 2006; 290: E780-788.
38. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M and Carling D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2005; 2: 21-33.
39. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR and Witters LA. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 2005; 280: 29060-29066.
40. Momcilovic M, Hong SP and Carlson M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 2006; 281: 25336-25343.
41. Li J, Miller EJ, Ninomiya-Tsuji J, Russell RR, 3rd and Young LH. AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart. Circ Res 2005; 97: 872-879.
42. Dyck JR, Kudo N, Barr AJ, Davies SP, Hardie DG and Lopaschuk GD. Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5′-AMP activated protein kinase. Eur J Biochem 1999; 262: 184-190.
43. Ojuka EO. Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle. Proc Nutr Soc 2004; 63: 275-278.
44. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D and Hue L. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 2000; 10: 1247-1255.
45. Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, Power DA, Ortiz de Montellano PR and Kemp BE. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 1999; 443: 285-289.
46. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-1657.
47. Duan C, Liimatta MB and Bottum OL. Insulin-like growth factor (IGF)-I regulates IGF-binding protein-5 gene expression through the phosphatidylinositol 3-kinase, protein kinase B/Akt, and p70 S6 kinase signaling pathway. J Biol Chem 1999; 274: 37147-37153.
48. Lorimer IA and Lavictoire SJ. Activation of extracellular-regulated kinases by normal and mutant EGF receptors. Biochim Biophys Acta 2001; 1538: 1-9.
49. Kattla JJ, Carew RM, Heljic M, Godson C and Brazil DP. Protein kinase B/ Akt activity is involved in renal TGF-beta1-driven epithelial-mesenchymal transition in vitro and in vivo. Am J Physiol Renal Physiol 2008; 295: F215-225.
50. Kitakaze M, Hori M, Takashima S, Sato H, Inoue M and Kamada T. Ischemic preconditioning increases adenosine release and 5′-nucleotidase activity during myocardial ischemia and reperfusion in dogs. Implications for myocardial salvage. Circulation 1993; 87: 208-215.
51. Regan SE, Broad M, Byford AM, Lankford AR, Cerniway RJ, Mayo MW and Matherne GP. A1 adenosine receptor overexpression attenuates ischemia-reperfusion-induced apoptosis and caspase 3 activity. Am J Physiol Heart Circ Physiol 2003; 284: H859-866.
52. Siddall HK, Warrell CE, Yellon DM and Mocanu MM. Ischemia-reperfusion injury and cardio-protection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency. Basic Res Cardiol 2008; 103: 560-568.
53. Mockridge JW, Marber MS and Heads RJ. Activation of Akt during simulated ischemia/reperfusion in cardiac myocytes. Biochem Biophys Res Commun 2000; 270: 947-952.
54. Ma H, Zhang HF, Yu L, Zhang QJ, Li J, Huo JH, Li X, Guo WY, Wang HC and Gao F. Vasculoprotective effect of insulin in the ischemic/reperfused canine heart: role of Akt-stimulated NO production. Cardiovasc Res 2006; 69: 57-65.
55. Tong H, Imahashi K, Steenbergen C and Murphy E. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective. Circ Res 2002; 90: 377-379.
56. Kwan HY, Huang Y and Yao X. Store-operated calcium entry in vascular endothelial cells is inhibited by cGMP via a protein kinase G-dependent mechanism. J Biol Chem 2000; 275: 6758-6763.
57. Ferrero R and Torres M. Prolonged exposure of chromaffin cells to nitric oxide down-regulates the activity of soluble guanylyl cyclase and corresponding mRNA and protein levels. BMC Biochem 2002; 3: 26.
58. Tong H, Rockman HA, Koch WJ, Steenbergen C and Murphy E. G protein-coupled receptor internalization signaling is required for cardioprotection in ischemic preconditioning. Circ Res 2004; 94: 1133-1141.
59. Murphy E, Wong R and Steenbergen C. Signalosomes: delivering cardioprotective signals from GPCRs to mitochondria. Am J Physiol Heart Circ Physiol 2008; 295: H920-H922.
60. Fryer RM, Hsu AK and Gross GJ. ERK and p38 MAP kinase activation are components of opioid-induced delayed cardioprotection. Basic Res Cardiol 2001; 96: 136-142.
61. Ping P, Zhang J, Cao X, Li RC, Kong D, Tang XL, Qiu Y, Manchikalapudi S, Auchampach JA, Black RG and Bolli R. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am J Physiol 1999; 276: H1468-1481.
62. Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995; 270: 1326-1331.
63. Tran SE, Holmstrom TH, Ahonen M, Kahari VM and Eriksson JE. MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. J Biol Chem 2001; 276: 16484-16490.
64. Boucher MJ, Morisset J, Vachon PH, Reed JC, Laine J and Rivard N. MEK/ ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 2000; 79: 355-369.
65. Zelivianski S, Spellman M, Kellerman M, Kakitelashvilli V, Zhou XW, Lugo E, Lee MS, Taylor R, Davis TL, Hauke R and Lin MF. ERK inhibitor PD98059 enhances docetaxel induced apoptosis of androgen-independent human prostate cancer cells. Int J Cancer 2003; 107: 478-485.
66. Yue TL, Wang C, Gu JL, Ma XL, Kumar S, Lee JC, Feuerstein GZ, Thomas H, Maleeff B and Ohlstein EH. Inhibition of extracellular signal-regulated kinase enhances Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ Res 2000; 86: 692-699.
67. Rezaie AR. Exosite-dependent regulation of the protein C anticoagulant pathway. Trends Cardiovasc Med 2003; 13: 8-15.
68. Foster DC, Yoshitake S and Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci U S A 1985; 82: 4673-4677.
69. Mather T, Oganessyan V, Hof P, Huber R, Foundling S, Esmon C and Bode W. The 2.8 A crystal structure of Gla-domainless activated protein C. Embo J 1996; 15: 6822-6831.
70. Stenflo J, Ohlin AK, Persson E, Valcarce C, Astermark J, Drakenberg T, Selander M, Linse S and Bjork I. Epidermal growth factor-like domains in the vitamin K-dependent clotting factors. Some structure-function relationships. Ann N Y Acad Sci 1991; 614: 11-29.
71. Oganesyan V, Oganesyan N, Terzyan S, Qu D, Dauter Z, Esmon NL and Esmon CT. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem 2002; 277: 24851-24854.
72. Riewald M and Schuepbach RA. Protective signaling pathways of activated protein C in endothelial cells. Arterioscler Thromb Vasc Biol 2008; 28: 1-3.
73. Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, Mizokami H and Kimoto M. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med 1998; 187: 1029-1035.
74. Esmon CT, Esmon NL, Le Bonniec BF and Johnson AE. Protein C activation. Methods Enzymol 1993; 222: 359-385.
75. Esmon CT. Molecular events that control the protein C anticoagulant pathway. Thromb Haemost 1993; 70: 29-35.
76. Laszik Z, Mitro A, Taylor FB, Jr., Ferrell G and Esmon CT. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 1997; 96: 3633-3640.
77. Smirnov MD, Ford DA, Esmon CT and Esmon NL. The effect of membrane composition on the hemostatic balance. Biochemistry 1999; 38: 3591-3598.
78. Egan JO, Kalafatis M and Mann KG. The effect of Arg306-->Ala and Arg506->Gln substitutions in the inactivation of recombinant human factor Va by activated protein C and protein S. Protein Sci 1997; 6: 2016-2027.
79. Riewald M, Petrovan RJ, Donner A, Mueller BM and Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-1882.
80. Ludeman MJ, Kataoka H, Srinivasan Y, Esmon NL, Esmon CT and Coughlin SR. PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem 2005; 280: 13122-13128.
81. Ide J, Aoki T, Ishivata S, Glusa E and Strukova SM. Proteinase-activated receptor agonists stimulate the increase in intracellular Ca2+ in cardiomyocytes and proliferation of cardiac fibroblasts from chick embryos. Bull Exp Biol Med 2007; 144: 760-763.
82. Ye X, Fukudome K, Tsuneyoshi N, Satoh T, Tokunaga O, Sugawara K, Mizokami H and Kimoto M. The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochem Biophys Res Commun 1999; 259: 671-677.
83. Sturn DH, Kaneider NC, Feistritzer C, Djanani A, Fukudome K and Wiedermann CJ. Expression and function of the endothelial protein C receptor in human neutrophils. Blood 2003; 102: 1499-1505.
84. Stephenson DA, Toltl LJ, Beaudin S and Liaw PC. Modulation of monocyte function by activated protein C, a natural anticoagulant. J Immunol 2006; 177: 2115-2122.
85. Zheng X, Li W, Song Y, Hu Y, Ferrell GL, Esmon NL and Esmon CT. Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 2007; 5: 1394-1400.
86. O'Brien LA, Richardson MA, Mehrbod SF, Berg DT, Gerlitz B, Gupta A and Grinnell BW. Activated protein C decreases tumor necrosis factor related apoptosis-inducing ligand by an EPCR- independent mechanism involving Egr-1/Erk-1/2 activation. Arterioscler Thromb Vasc Biol 2007; 27: 2634-2641.
87. Esmon CT. The anticoagulant and anti-inflammatory roles of the protein C anticoagulant pathway. J Autoimmun 2000; 15: 113-116.
88. Iwaki T, Cruz DT, Martin JA and Castellino FJ. A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse. Blood 2005; 105: 2364-2371.
89. Taylor FB, Jr., Stearns-Kurosawa DJ, Kurosawa S, Ferrell G, Chang AC, Laszik Z, Kosanke S, Peer G and Esmon CT. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95: 1680-1686.
90. Galligan L, Livingstone W, Volkov Y, Hokamp K, Murphy C, Lawler M, Fukudome K and Smith O. Characterization of protein C receptor expression in monocytes. Br J Haematol 2001; 115: 408-414.
91. Schmidt-Supprian M, Murphy C, While B, Lawler M, Kapurniotu A, Voelter W, Smith O and Bernhagen J. Activated protein C inhibits tumor necrosis factor and macrophage migration inhibitory factor production in monocytes. Eur Cytokine Netw 2000; 11: 407-413.
92. Joyce DE and Grinnell BW. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med 2002; 30: S288-293.
93. Domotor E, Benzakour O, Griffin JH, Yule D, Fukudome K and Zlokovic BV. Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1. Blood 2003; 101: 4797-4801.
94. Gateau-Roesch O, Argaud L and Ovize M. Mitochondrial permeability transition pore and postconditioning. Cardiovasc Res 2006; 70: 264-273.
95. Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K and Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003; 9: 338-342.
96. Liu D, Cheng T, Guo H, Fernandez JA, Griffin JH, Song X and Zlokovic BV. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med 2004; 10: 1379-1383.
97. Griffin JH, Fernandez JA, Liu D, Cheng T, Guo H and Zlokovic BV. Activated protein C and ischemic stroke. Crit Care Med 2004; 32: S247-253.
98. Shibata M, Kumar SR, Amar A, Fernandez JA, Hofman F, Griffin JH and Zlokovic BV. Anti inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 2001; 103: 1799-1805.
99. Mizutani A, Okajima K, Uchiba M and Noguchi T. Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 2000; 95: 3781-3787.
100. Hirose K, Okajima K, Taoka Y, Uchiba M, Tagami H, Nakano K, Utoh J, Okabe H and Kitamura N. Activated protein C reduces the ischemia/ reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation. Ann Surg 2000; 232: 272-280.
101. Laffan MA. Activated protein C resistance and myocardial infarction. Heart 1998; 80: 319-321.
102. Samani NJ, Lodwick D, Martin D and Kimber P. Resistance to activated protein C and risk of premature myocardial infarction. Lancet 1994; 344: 1709-1710.
103. Norlund L, Holm J, Zoller B and Ohlin AK. A common thrombomodulin amino acid dimorphism is associated with myocardial infarction. Thromb Haemost 1997; 77: 248-251.
104. Ireland H, Kunz G, Kyriakoulis K, Stubbs PJ and Lane DA. Thrombomodulin gene mutations associated with myocardial infarction. Circulation 1997; 96: 15-18.
105. Medina P, Navarro S, Corral J, Zorio E, Roldan V, Estelles A, Santamaria A, Marin F, Rueda J, Bertina RM and Espana F. Endothelial protein C receptor polymorphisms and risk of myocardial infarction. Haematologica 2008; 93: 1358-1363.
106. Fernandez JA, Vento AE, Jormalainen M, Griffin JH, Pesonen E, Syrjala M, Repo H, Jansson SE, Ramo OJ and Petaja J. Activated protein C in the cardioplegic solution on a porcine model of coronary ischemia-reperfusion has deleterious hemodynamic effects. Cardiovasc Drugs Ther 2006; 20: 113-121.
107. Pirat B, Muderrisoglu H, Unal MT, Ozdemir H, Yildirir A, Yucel M and Turkoglu S. Recombinant human-activated protein C inhibits cardiomyocyte apoptosis in a rat model of myocardial ischemia-reperfusion. Coron Artery Dis 2007; 18: 61-66.