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CC BY-NC-ND 4.0 · TH Open 2017; 01(01): e24-e32
DOI: 10.1055/s-0037-1603928
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Platelets Protect Cardiomyocytes from Ischemic Damage

Tony G. Walsh
1   School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom
,
Alastair W. Poole
1   School of Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom
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Publikationsdatum:
28. Juni 2017 (online)

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Abstract

Platelets are classically known for their roles in bleeding control and occlusive thrombus formation causing ischemic tissue damage. Recently, nonclassical roles for platelets have been described, many of which may be mediated by the heterogeneous cargo that platelets secrete from granular stores upon activation. Using an in vitro model of ischemic injury to ventricular cardiomyocytes, we observed that platelets, through secreted factors, delayed the rate of cardiomyocyte death during ischemia. This protective effect appeared independent of platelet dense granule cargo, but required α-granule components stromal cell-derived factor-1α and transforming growth factor-β1. Protein kinase C activity within cardiomyocytes was responsible for mediating the protective signals initiated by the released platelet cargo. Importantly, pretreating platelets with a P2Y12 antagonist, but not the cyclooxygenase inhibitor aspirin, substantially attenuated this protective effect. These findings therefore reveal a paradoxically protective role for platelet activation during cardiac ischemia and could have important implications for the use of antiplatelet therapeutics in the management of myocardial infarction.

Keywords

platelets - secretion - thrombosis - cardiomyocytes - ischemia

Funding

This work was funded by grants from the British Heart Foundation to A.W.P. (PG/13/14/30023, RG/10/006/28299, RG/15/16/31758).


Supplementary Material

 

  • References

  • 1 Rafii S, Cao Z, Lis R. , et al. Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. Nat Cell Biol 2015; 17 (02) 123-136
    CrossrefPubMedGoogle Scholar
  • 2 Lynch SE, Nixon JC, Colvin RB, Antoniades HN. Role of platelet-derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci U S A 1987; 84 (21) 7696-7700
    CrossrefPubMedGoogle Scholar
  • 3 Xiang B, Zhang G, Guo L. , et al. Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway. Nat Commun 2013; 4: 2657
    CrossrefPubMedGoogle Scholar
  • 4 Jørgensen L. The role of platelets in the initial stages of atherosclerosis. J Thromb Haemost 2006; 4 (07) 1443-1449
    CrossrefPubMedGoogle Scholar
  • 5 Ho-Tin-Noé B, Goerge T, Cifuni SM, Duerschmied D, Wagner DD. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res 2008; 68 (16) 6851-6858
    CrossrefPubMedGoogle Scholar
  • 6 Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59 (06) 1295-1300
    PubMedGoogle Scholar
  • 7 Coppinger JA, Cagney G, Toomey S. , et al. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 2004; 103 (06) 2096-2104
    CrossrefPubMedGoogle Scholar
  • 8 Golebiewska EM, Poole AW. Secrets of platelet exocytosis - what do we really know about platelet secretion mechanisms?. Br J Haematol 2013; 165 (02) 204-216
    CrossrefPubMedGoogle Scholar
  • 9 Walsh TG, Metharom P, Berndt MC. The functional role of platelets in the regulation of angiogenesis. Platelets 2015; 26 (03) 199-211
    CrossrefPubMedGoogle Scholar
  • 10 Pachel C, Mathes D, Arias-Loza AP. , et al. Inhibition of platelet glycoprotein VI protects against myocardial ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol 2016; 36 (04) 629-635
    CrossrefPubMedGoogle Scholar
  • 11 Devanathan V, Hagedorn I, Köhler D. , et al. Platelet Gi protein Gαi2 is an essential mediator of thrombo-inflammatory organ damage in mice. Proc Natl Acad Sci U S A 2015; 112 (20) 6491-6496
    CrossrefPubMedGoogle Scholar
  • 12 Yang BC, Mehta JL. Platelet-derived adenosine contributes to the cardioprotective effects of platelets against ischemia-reperfusion injury in isolated rat heart. J Cardiovasc Pharmacol 1994; 24 (05) 779-785
    CrossrefPubMedGoogle Scholar
  • 13 Yang BC, Virmani R, Nichols WW, Mehta JL. Platelets protect against myocardial dysfunction and injury induced by ischemia and reperfusion in isolated rat hearts. Circ Res 1993; 72 (06) 1181-1190
    CrossrefPubMedGoogle Scholar
  • 14 Parodi EM, Kuhn B. Signalling between microvascular endothelium and cardiomyocytes through neuregulin. Cardiovasc Res 2014; 102 (02) 194-204
    CrossrefPubMedGoogle Scholar
  • 15 Harper MT, van den Bosch MT, Hers I, Poole AW. Absence of platelet phenotype in mice lacking the motor protein myosin Va. PLoS One 2013; 8 (01) e53239
    CrossrefPubMedGoogle Scholar
  • 16 Vander Heide RS, Rim D, Hohl CM, Ganote CE. An in vitro model of myocardial ischemia utilizing isolated adult rat myocytes. J Mol Cell Cardiol 1990; 22 (02) 165-181
    CrossrefPubMedGoogle Scholar
  • 17 Wang F, He Q, Sun Y, Dai X, Yang XP. Female adult mouse cardiomyocytes are protected against oxidative stress. Hypertension 2010; 55 (05) 1172-1178
    CrossrefPubMedGoogle Scholar
  • 18 Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res 2004; 61 (03) 498-511
    CrossrefPubMedGoogle Scholar
  • 19 Savage JS, Williams CM, Konopatskaya O, Hers I, Harper MT, Poole AW. Munc13-4 is critical for thrombosis through regulating release of ADP from platelets. J Thromb Haemost 2013; 11 (04) 771-775
    CrossrefPubMedGoogle Scholar
  • 20 Hu X, Dai S, Wu WJ. , et al. Stromal cell derived factor-1 alpha confers protection against myocardial ischemia/reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis. Circulation 2007; 116 (06) 654-663
    CrossrefPubMedGoogle Scholar
  • 21 Yang BC, Zander DS, Mehta JL. Hypoxia-reoxygenation-induced apoptosis in cultured adult rat myocytes and the protective effect of platelets and transforming growth factor-beta(1). J Pharmacol Exp Ther 1999; 291 (02) 733-738
    PubMedGoogle Scholar
  • 22 Döring Y, Pawig L, Weber C, Noels H. The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease. Front Physiol 2014; 5: 212
    PubMedGoogle Scholar
  • 23 Koitabashi N, Danner T, Zaiman AL. , et al. Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload. J Clin Invest 2011; 121 (06) 2301-2312
    CrossrefPubMedGoogle Scholar
  • 24 Gardiner EE, De Luca M, McNally T, Michelson AD, Andrews RK, Berndt MC. Regulation of P-selectin binding to the neutrophil P-selectin counter-receptor P-selectin glycoprotein ligand-1 by neutrophil elastase and cathepsin G. Blood 2001; 98 (05) 1440-1447
    CrossrefPubMedGoogle Scholar
  • 25 Henn V, Slupsky JR, Gräfe M. , et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391 (6667): 591-594
    CrossrefPubMedGoogle Scholar
  • 26 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74 (05) 1124-1136
    CrossrefPubMedGoogle Scholar
  • 27 Armstrong S, Ganote CE. Preconditioning of isolated rabbit cardiomyocytes: effects of glycolytic blockade, phorbol esters, and ischaemia. Cardiovasc Res 1994; 28 (11) 1700-1706
    CrossrefPubMedGoogle Scholar
  • 28 Armstrong SC, Kao R, Gao W. , et al. Comparison of in vitro preconditioning responses of isolated pig and rabbit cardiomyocytes: effects of a protein phosphatase inhibitor, fostriecin. J Mol Cell Cardiol 1997; 29 (11) 3009-3024
    CrossrefPubMedGoogle Scholar
  • 29 Ren Q, Wimmer C, Chicka MC. , et al. Munc13-4 is a limiting factor in the pathway required for platelet granule release and hemostasis. Blood 2010; 116 (06) 869-877
    CrossrefPubMedGoogle Scholar
  • 30 King SM, McNamee RA, Houng AK, Patel R, Brands M, Reed GL. Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice. Circulation 2009; 120 (09) 785-791
    CrossrefPubMedGoogle Scholar
  • 31 Colgan SP, Eltzschig HK, Eckle T, Thompson LF. Physiological roles for ecto-5′-nucleotidase (CD73). Purinergic Signal 2006; 2 (02) 351-360
    CrossrefPubMedGoogle Scholar
  • 32 Heijnen H, van der Sluijs P. Platelet secretory behaviour: as diverse as the granules … or not?. J Thromb Haemost 2015; 13 (12) 2141-2151
    CrossrefPubMedGoogle Scholar
  • 33 Jonnalagadda D, Izu LT, Whiteheart SW. Platelet secretion is kinetically heterogeneous in an agonist-responsive manner. Blood 2012; 120 (26) 5209-5216
    CrossrefPubMedGoogle Scholar
  • 34 Italiano Jr JE, Richardson JL, Patel-Hett S. , et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111 (03) 1227-1233
    PubMedGoogle Scholar
  • 35 Gong Q, Pitas RE. Synergistic effects of growth factors on the regulation of smooth muscle cell scavenger receptor activity. J Biol Chem 1995; 270 (37) 21672-21678
    CrossrefPubMedGoogle Scholar
  • 36 Fryer RM, Pratt PF, Hsu AK, Gross GJ. Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. J Pharmacol Exp Ther 2001; 296 (02) 642-649
    PubMedGoogle Scholar
  • 37 Kunuthur SP, Mocanu MM, Hemmings BA, Hausenloy DJ, Yellon DM. The Akt1 isoform is an essential mediator of ischaemic preconditioning. J Cell Mol Med 2012; 16 (08) 1739-1749
    CrossrefPubMedGoogle Scholar
  • 38 Fryer RM, Schultz JE, Hsu AK, Gross GJ. Importance of PKC and tyrosine kinase in single or multiple cycles of preconditioning in rat hearts. Am J Physiol 1999; 276 (4, Pt 2): H1229-H1235
    PubMedGoogle Scholar
  • 39 Ytrehus K, Liu Y, Downey JM. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol 1994; 266 (3, Pt 2): H1145-H1152
    PubMedGoogle Scholar
  • 40 Lim JY, Park SJ, Hwang HY. , et al. TGF-beta1 induces cardiac hypertrophic responses via PKC-dependent ATF-2 activation. J Mol Cell Cardiol 2005; 39 (04) 627-636
    CrossrefPubMedGoogle Scholar
  • 41 Odemis V, Boosmann K, Dieterlen MT, Engele J. The chemokine SDF1 controls multiple steps of myogenesis through atypical PKCzeta. J Cell Sci 2007; 120 (Pt 22): 4050-4059
    CrossrefPubMedGoogle Scholar
  • 42 Halestrap AP, Clarke SJ, Khaliulin I. The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta 2007; 1767 (08) 1007-1031
    CrossrefPubMedGoogle Scholar
  • 43 Suzuki M, Sasaki N, Miki T. , et al. Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest 2002; 109 (04) 509-516
    CrossrefPubMedGoogle Scholar
  • 44 Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov 2010; 9 (02) 154-169
    CrossrefPubMedGoogle Scholar
  • 45 Fu Y, Wang Z, Chen WL, Moore PK, Zhu YZ. Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats. Am J Physiol Heart Circ Physiol 2007; 293 (03) H1545-H1552
    CrossrefPubMedGoogle Scholar
  • 46 Bell RM, Sivaraman V, Kunuthur SP, Cohen MV, Downey JM, Yellon DM. Cardioprotective properties of the platelet P2Y12 receptor inhibitor, Cangrelor: protective in diabetics and reliant upon the presence of blood. Cardiovasc Drugs Ther 2015; 29 (05) 415-418
    CrossrefPubMedGoogle Scholar
  • 47 Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y. Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol 2015; 35 (08) 1805-1814
    CrossrefPubMedGoogle Scholar
  • 48 Nanhwan MK, Ling S, Kodakandla M, Nylander S, Ye Y, Birnbaum Y. Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. Arterioscler Thromb Vasc Biol 2014; 34 (09) 2078-2085
    CrossrefPubMedGoogle Scholar
  • 49 Diaz RJ, Wilson GJ. Studying ischemic preconditioning in isolated cardiomyocyte models. Cardiovasc Res 2006; 70 (02) 286-296
    CrossrefPubMedGoogle Scholar
  • 50 Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release. Proc Natl Acad Sci U S A 2001; 98 (11) 6470-6475
    CrossrefPubMedGoogle Scholar