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New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications

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Abstract

Altered platelet physiology may contribute to the emergence of thrombosis in patients with many forms of cardiovascular disease. Excess platelet activation may reflect increased stimulation of pro-aggregatory pathways. There is, however, increasing evidence that excessive platelet response, due to impaired efficacy of anti-aggregatory autacoids such as nitric oxide (NO) and prostacyclin (PGI2), may be just as important. For example, diminished platelet response to NO has been documented in acute and chronic myocardial ischaemia, heart failure, aortic valve disease and in the presence of hyperglycaemia. This “NO resistance” has been shown to reflect both the scavenging of NO by reactive oxygen species and dysfunction of its intracellular “receptor”, soluble guanylate cyclase. Importantly, these abnormalities of NO signalling are potentially reversible through judicious application of pharmacotherapy. The analogous condition of impaired PGI2/adenylate cyclase (AC) signalling has received comparatively less attention to date. We have shown that platelet response to prostaglandin E1 (PGE1) is frequently impaired in patients with symptomatic myocardial ischaemia. Because the effects of ADP receptor antagonists such as clopidogrel and ticagrelor at the level of the P2Y12 receptor are coupled with changes in activity of AC, impaired response to PGE1 might imply both increased thrombotic risk and a reduced efficacy of anti-aggregatory drugs. Accordingly, patient response to treatment with clopidogrel is determined not only by variability of clopidogrel bio-activation, but also extensively by the integrity of platelet AC signalling. We here review these recent developments and their emerging therapeutic implications for thrombotic disorders.

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References

  1. Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost. 2009;102(2):248–57.

    CAS  PubMed  Google Scholar 

  2. Hurst NL, Nooney VB, Raman B, Chirkov YY, De Caterina R, Horowitz JD. Clopidogrel "resistance": pre- vs post-receptor determinants. Vasc Pharmacol. 2013;59(5–6):152–61.

    Article  CAS  Google Scholar 

  3. Procter NE, Chong CR, Sverdlov AL, Chan WP, Chirkov YY, Horowitz JD. Aging of platelet nitric oxide signaling: pathogenesis, clinical implications, and therapeutics. Semin Thromb Hemost. 2014;40(6):660–8.

    Article  CAS  PubMed  Google Scholar 

  4. Ault KA, Cannon CP, Mitchell J, McCahan J, Tracy RP, Novotny WF, et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in myocardial infarction. J Am Coll Cardiol. 1999;33(3):634–9.

    Article  CAS  PubMed  Google Scholar 

  5. Kamath S, Blann AD, Chin BS, Lanza F, Aleil B, Cazenave JP, et al. A study of platelet activation in atrial fibrillation and the effects of antithrombotic therapy. Eur Heart J. 2002;23(22):1788–95.

    Article  CAS  PubMed  Google Scholar 

  6. Ohara K, Inoue H, Nozawa T, Hirai T, Iwasa A, Okumura K, et al. Accumulation of risk factors enhances the prothrombotic state in atrial fibrillation. Int J Cardiol. 2008;126(3):316–21.

    Article  PubMed  Google Scholar 

  7. Gurbel PA, Gattis WA, Fuzaylov SF, Gaulden L, Hasselblad V, Serebruany VL, et al. Evaluation of platelets in heart failure: is platelet activity related to etiology, functional class, or clinical outcomes? Am Heart J. 2002;143(6):1068–75.

    Article  PubMed  Google Scholar 

  8. Chirkov YY, Holmes AS, Willoughby SR, Stewart S, Wuttke RD, Sage PR, et al. Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets. J Am Coll Cardiol. 2001;37(7):1851–7.

    Article  CAS  PubMed  Google Scholar 

  9. Procter NE, Ball J, Liu S, Hurst N, Nooney VB, Goh V et al. Impaired platelet nitric oxide response in patients with new onset atrial fibrillation. Int J Cardiol 2015;179(0):160–165.

  10. Chirkov YY, Holmes AS, Martelli JD, Horowitz JD. Effect of perindopril on platelet nitric oxide resistance in patients with chronic heart failure secondary to ischemic left ventricular dysfunction. Am J Cardiol. 2004;93(11):1438–40 .A10

    Article  CAS  PubMed  Google Scholar 

  11. Worthley MI, Holmes AS, Willoughby SR, Kucia AM, Heresztyn T, Stewart S, et al. The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes mediation by superoxide production, resolution with intensive insulin administration. J Am Coll Cardiol. 2007;49(3):304–10.

    Article  CAS  PubMed  Google Scholar 

  12. Anfossi G, Russo I, Massucco P, Mattiello L, Doronzo G, De Salve A, et al. Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity. Eur J Clin Investig. 2004;34(7):482–9.

    Article  CAS  Google Scholar 

  13. Chirkov YY, Chirkova LP, Sage RE, Horowitz JD. Impaired responsiveness of platelets from patients with stable angina pectoris to antiaggregating and cyclicAMP-elevating effects of prostaglandin E1. J Cardiovasc Pharmacol. 1995;25(6):961–6.

    Article  CAS  PubMed  Google Scholar 

  14. Chirkov YY, Horowitz JD. Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier? Pharmacol Ther. 2007;116(2):287–305.

    Article  CAS  PubMed  Google Scholar 

  15. Chong CR, Liu S, Licari G, Heresztyn T, Chirkov YY, Ngo DT, et al. Reversal of hyperglycemia: effects on nitric oxide signaling. Am J Med. 2015;128(4):427–30.

    Article  CAS  PubMed  Google Scholar 

  16. Rajendran S, Willoughby SR, Chan WP, Liberts EA, Heresztyn T, Saha M, et al. Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects. Atherosclerosis. 2009;204(2):509–14.

    Article  CAS  PubMed  Google Scholar 

  17. Chan WP, Ngo DT, Sverdlov AL, Rajendran S, Stafford I, Heresztyn T, et al. Premature aging of cardiovascular/platelet function in polycystic ovarian syndrome. Am J Med. 2013;126(7):640 e1–7.

    Article  PubMed  Google Scholar 

  18. Stepien JM, Prideaux RM, Willoughby SR, Chirkov YY, Horowitz JD. Pilot study examining the effect of cholesterol lowering on platelet nitric oxide responsiveness and arterial stiffness in subjects with isolated mild hypercholesterolaemia. Clin Exp Pharmacol Physiol. 2003;30(7):507–12.

    Article  CAS  PubMed  Google Scholar 

  19. Ngo DT, Sverdlov AL, Willoughby SR, Nightingale AK, Chirkov YY, McNeil JJ, et al. Determinants of occurrence of aortic sclerosis in an aging population. J Am Coll Cardiol Img. 2009;2(8):919–27.

    Article  Google Scholar 

  20. Bergandi L, Cordero M, Anselmino M, Ferraro G, Ravera L, Dalmasso P, et al. Altered nitric oxide/cGMP platelet signaling pathway in platelets from patients with acute coronary syndromes. Clin Res Cardiol. 2010;99(9):557–64.

    Article  CAS  PubMed  Google Scholar 

  21. Sverdlov AL, Ngo DT, Horowitz JD. Pathogenesis of aortic sclerosis: association with low BMI, tissue nitric oxide resistance, but not systemic inflammatory activation. Am J Cardiovasc Dis. 2012;2(1):43–9.

    CAS  PubMed  Google Scholar 

  22. Erdmann J, Stark K, Esslinger UB, Rumpf PM, Koesling D, de Wit C, et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature. 2013;504(7480):432–6.

    Article  CAS  PubMed  Google Scholar 

  23. Sayed N, Baskaran P, Ma X, van den Akker F, Beuve A. Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation. Proc Natl Acad Sci U S A. 2007;104(30):12312–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sayed N, Kim DD, Fioramonti X, Iwahashi T, Duran WN, Beuve A. Nitroglycerin-induced S-nitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance. Circ Res. 2008;103(6):606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Maron BA, Zhang YY, Handy DE, Beuve A, Tang SS, Loscalzo J, et al. Aldosterone increases oxidant stress to impair guanylyl cyclase activity by cysteinyl thiol oxidation in vascular smooth muscle cells. J Biol Chem. 2009;284(12):7665–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chirkov YY, Chirkova LP, Horowitz JD. Nitroglycerin tolerance at the platelet level in patients with angina pectoris. Am J Cardiol. 1997;80(2):128–31.

    Article  CAS  PubMed  Google Scholar 

  27. Ignarro LJ, Degnan JN, Baricos WH, Kadowitz PJ, Wolin MS. Activation of purified guanylate cyclase by nitric oxide requires heme. Comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung. Biochim Biophys Acta. 1982;718(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  28. Mellion BT, Ignarro LJ, Myers CB, Ohlstein EH, Ballot BA, Hyman AL, et al. Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. Mol Pharmacol. 1983;23(3):653–64.

    CAS  PubMed  Google Scholar 

  29. Magwenzi S, Woodward C, Wraith KS, Aburima A, Raslan Z, Jones H, et al. Oxidized LDL activates blood platelets through CD36/NOX2-mediated inhibition of the cGMP/protein kinase G signaling cascade. Blood. 2015;125(17):2693–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Webb DJ, Muirhead GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol. 2000;36(1):25–31.

    Article  CAS  PubMed  Google Scholar 

  31. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation. 2007;116(3):238–48.

    Article  CAS  PubMed  Google Scholar 

  32. Farrow KN, Wedgwood S, Lee KJ, Czech L, Gugino SF, Lakshminrusimha S, et al. Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn. Respir Physiol Neurobiol. 2010;174(3):272–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pinto C, Papa D, Hubner M, Mou TC, Lushington GH, Seifert R. Activation and inhibition of adenylyl cyclase isoforms by forskolin analogs. J Pharmacol Exp Ther. 2008;325(1):27–36.

    Article  CAS  PubMed  Google Scholar 

  34. Steegborn C. Structure, mechanism, and regulation of soluble adenylyl cyclases - similarities and differences to transmembrane adenylyl cyclases. Biochim Biophys Acta. 2014;1842(12 Pt B):2535–47.

    Article  CAS  PubMed  Google Scholar 

  35. Bassenge E, Pohl U, Busse R. Generation and transmission of vasoactive and antiaggregatory signals by the endothelium. Adv Second Messenger Phosphoprotein Res. 1990;24:434–40.

    CAS  PubMed  Google Scholar 

  36. Paul BZ, Ashby B, Sheth SB. Distribution of prostaglandin IP and EP receptor subtypes and isoforms in platelets and human umbilical artery smooth muscle cells. Br J Haematol. 1998;102(5):1204–11.

    Article  CAS  PubMed  Google Scholar 

  37. Lagarde M, Berciaud P, Burtin M, Dechavanne M. Refractoriness of diabetic platelets to inhibitory prostaglandins. Prostaglandins Med. 1981;7(4):341–7.

    Article  CAS  PubMed  Google Scholar 

  38. Akai T, Naka K, Okuda K, Takemura T, Fujii S. Decreased sensitivity of platelets to prostacyclin in patients with diabetes mellitus. Horm Metab Res. 1983;15(11):523–6.

    Article  CAS  PubMed  Google Scholar 

  39. Onodera H, Hirata T, Sugawara H, Sugai K, Yoda B, Toyota T, et al. Platelet sensitivity to adenosine diphosphate and to prostacyclin in diabetic patients. Tohoku J Exp Med. 1982;137(4):423–8.

    Article  CAS  PubMed  Google Scholar 

  40. Russo I, Traversa M, Bonomo K, De Salve A, Mattiello L, Del Mese P, et al. In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin. Obesity. 2010;18(4):788–97.

    Article  CAS  PubMed  Google Scholar 

  41. Willoughby SR, Stewart S, Holmes AS, Chirkov YY, Horowitz JD. Platelet nitric oxide responsiveness: a novel prognostic marker in acute coronary syndromes. Arterioscler Thromb Vasc Biol. 2005;25(12):2661–6.

    Article  CAS  PubMed  Google Scholar 

  42. Iyu D, Glenn JR, White AE, Johnson AJ, Fox SC, Heptinstall S. The role of prostanoid receptors in mediating the effects of PGE(2) on human platelet function. Platelets. 2010;21(5):329–42.

    Article  CAS  PubMed  Google Scholar 

  43. Mahaffey KW, Wojdyla DM, Carroll K, Becker RC, Storey RF, Angiolillo DJ, et al. Ticagrelor compared with clopidogrel by geographic region in the platelet inhibition and patient outcomes (PLATO) trial. Circulation. 2011;124(5):544–54.

    Article  CAS  PubMed  Google Scholar 

  44. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent anticoagulation restenosis study investigators. N Engl J Med. 1998;339(23):1665–71.

    Article  CAS  PubMed  Google Scholar 

  45. Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334(17):1084–9.

    Article  CAS  PubMed  Google Scholar 

  46. Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? J Am Coll Cardiol. 2007;49(6):657–66.

    Article  CAS  PubMed  Google Scholar 

  47. Aradi D, Rideg O, Vorobcsuk A, Magyarlaki T, Magyari B, Konyi A, et al. Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity. Eur J Clin Investig. 2012;42(4):384–92.

    Article  CAS  Google Scholar 

  48. Aleil B, Jacquemin L, De Poli F, Zaehringer M, Collet JP, Montalescot G, et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (vasodilator-stimulated phosphoprotein-02) randomized study. J Am Coll Cardiol Intv. 2008;1(6):631–8.

    Article  Google Scholar 

  49. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ. 2011;343:d4588.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Frelinger 3rd AL, Bhatt DL, Lee RD, Mulford DJ, Wu J, Nudurupati S, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61(8):872–9.

    Article  CAS  PubMed  Google Scholar 

  52. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49(14):1505–16.

    Article  CAS  PubMed  Google Scholar 

  53. Nooney VB, Hurst NL, Chirkov YY, De Caterina R, Horowitz JD. Post receptor determinants of acute platelet response to clopidogrel in patients with symptomatic myocardial ischemia. Vasc Pharmacol 2015;65–66:17–22.

  54. Hurst NL, Nooney VB, Chirkov YY, De Caterina R, Horowitz JD. Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling. Thromb Res. 2015;136(2):308–14.

    Article  CAS  PubMed  Google Scholar 

  55. Iyu D, Glenn JR, White AE, Fox SC, Dovlatova N, Heptinstall S. P2Y(1)(2) and EP3 antagonists promote the inhibitory effects of natural modulators of platelet aggregation that act via cAMP. Platelets. 2011;22(7):504–15.

    Article  CAS  PubMed  Google Scholar 

  56. Michelson AD. Platelets. 2nd ed. Amsterdam. Boston: Academic Press/Elsevier; 2007.

    Google Scholar 

  57. Cattaneo M, Zighetti ML, Lombardi R, Martinez C, Lecchi A, Conley PB, et al. Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Proc Natl Acad Sci U S A. 2003;100(4):1978–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Raslan Z, Naseem KM. Compartmentalisation of cAMP-dependent signalling in blood platelets: the role of lipid rafts and actin polymerisation. Platelets. 2015;26(4):349–57.

    Article  CAS  PubMed  Google Scholar 

  59. Iyu D, Juttner M, Glenn JR, White AE, Johnson AJ, Fox SC, et al. PGE1 and PGE2 modify platelet function through different prostanoid receptors. Prostaglandins Other Lipid Mediat. 2011;94(1–2):9–16.

    Article  CAS  PubMed  Google Scholar 

  60. Burkhart JM, Vaudel M, Gambaryan S, Radau S, Walter U, Martens L, et al. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood. 2012;120(15):e73–82.

    Article  CAS  PubMed  Google Scholar 

  61. Katsel PL, Tagliente TM, Schwarz TE, Craddock-Royal BD, Patel ND, Maayani S. Molecular and biochemical evidence for the presence of type III adenylyl cyclase in human platelets. Platelets. 2003;14(1):21–33.

    Article  CAS  PubMed  Google Scholar 

  62. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol. 2010;70(1):65–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153(1):66 e9–16.

    Article  PubMed  Google Scholar 

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Acknowledgments

N.L. Hurst, H. Imam and V.B. Nooney were supported in part by postgraduate research fellowships from The University of Adelaide and The University of South Australia.

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Authors and Affiliations

  1. Basil Hetzel Institute for Translational Research, The Queen Elizabeth Hospital, The University of Adelaide, Cardiology Unit, 28 Woodville Rd, Woodville South, Adelaide, SA, 5011, Australia

    Nathan E. K. Procter, Nicola L. Hurst, Hasan Imam, Yuliy Y. Chirkov & John D. Horowitz

  2. Basil Hetzel Institute for Translational Research, The Queen Elizabeth Hospital, The University of South Australia, Adelaide, Australia

    Vivek B. Nooney

  3. Institute of Cardiology and Centre for Excellence on Aging, “G. d’Annunzio” University, Chieti, Italy

    Raffaele De Caterina

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  1. Nathan E. K. Procter
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  2. Nicola L. Hurst
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  4. Hasan Imam
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  5. Raffaele De Caterina
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  6. Yuliy Y. Chirkov
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  7. John D. Horowitz
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Correspondence to John D. Horowitz.

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Procter, N.E.K., Hurst, N.L., Nooney, V.B. et al. New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications. Cardiovasc Drugs Ther 30, 505–513 (2016). https://doi.org/10.1007/s10557-016-6671-4

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