Taming platelets with cyclic nucleotides

Citation
Ur. Schwarz et al., Taming platelets with cyclic nucleotides, BIOCH PHARM, 62(9), 2001, pp. 1153-1161
Citations number
73
Language
INGLESE
art.tipo
Editorial Material
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
9
Year of publication
2001
Pages
1153 - 1161
Database
ISI
SICI code
0006-2952(20011101)62:9<1153:TPWCN>2.0.ZU;2-Z
Abstract
Cardiovascular diseases are often accompanied and aggravated by pathologic platelet activation. Tight regulation of platelet function is an essential prerequisite for intact vessel physiology or effective cardiovascular thera py. Physiological platelet antagonists as well as various pharmacological v asodilators inhibit platelet function by activating adenylyl and guanylyl c yclases and increasing intracellular cyclic AMP (cAMP) and cyclic GMP (cGMP ) levels, respectively. Elevation of platelet cyclic nucleotides interferes with basically all known platelet activatory signaling pathways, and effec tively blocks complex intracellular signaling networks, cytoskeletal rearra ngements, fibrinogen receptor activation, degranulation, and expression of pro-inflammatory signaling molecules. The major target molecules of cyclic nucleotides in platelets are cyclic nucleotide-dependent protein kinases th at mediate their effects through phosphorylation of specific substrates. Th ey directly affect receptor/G-protein activation and interfere with a varie ty of signal transduction pathways, including the phospholipase C, protein kinase C, and mitogen-activated protein kinase pathways. Regulation of thes e pathways blocks several steps of cytosolic Ca2+ elevation and controls a multitude of cytoskeleton-associated proteins that are directly involved in organization of the platelet cytoskeleton. Due to their multiple sites of action and strong inhibitory potencies, cyclic nucleotides and their regula tory pathways are of particular interest for developing new approaches for the treatment of thrombotic and cardiovascular disorders. (C) 2001 Elsevier Science Inc. All rights reserved.