title: New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications.
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 P2Y12receptor are coupled with changes in activity of AC, impaired response to PGE1might 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.
authors.affiliation: 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.
authors.forename: Nathan E K
authors.initials: NE
authors.lastname: Procter
authors.affiliation: 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.
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Hurst
authors.affiliation: Basil Hetzel Institute for Translational Research, The Queen Elizabeth Hospital, The University of South Australia, Adelaide, Australia.
authors.forename: Vivek B
authors.initials: VB
authors.lastname: Nooney
authors.affiliation: 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.
authors.forename: Hasan
authors.initials: H
authors.lastname: Imam
authors.affiliation: Institute of Cardiology and Centre for Excellence on Aging, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
authors.affiliation: 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.
authors.forename: Yuliy Y
authors.initials: YY
authors.lastname: Chirkov
authors.affiliation: 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. john.horowitz@adelaide.edu.au.
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000527:Alprostadil / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D009712:Nucleotides, Cyclic / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D009712:Nucleotides, Cyclic; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D000527:Alprostadil
keywords: Adenylate cyclase; Clopidogrel; Nitric oxide; Platelet; Prostacyclin; Soluble guanylate cyclase