Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent purification of a vasodilator-stimulated phosphoprotein (VASP) from human platelets and the development of a specific antiserum against VASP made it possible to study the quantitative effects of cAMP-elevating prostaglandins on cAMP-mediated phosphorylation of VASP in intact human platelets. Prostacyclin (PG-I2), prostaglandin-E1 (PG-E1) and the stable prostacyclinanalog Iloprost, all agents used for the treatment of peripheral vascular disease, induced rapid, stoichiometric and reversible phosphorylation of VASP in human platelets mediated by the cAMP-dependent protein kinase. However, there were substantial differences between these three cAMP-elevating prostaglandins with respect to their effects on extent, duration and reversibility of VASP phosphorylation. Maximal VASP phosphorylation was induced both by PG-I2 and Iloprost, but the PG-I2 effect was only of short duration in comparison to that of Iloprost. The extent of PG-E1-induced VASP phosphorylation was less than that observed with PG-I2 and Iloprost. In endothelial cell-platelet coincubations, an endothelial cell-derived, indomethacin-sensitive factor caused a rapid elevation of platelet cAMP level and VASP phosphorylation. These results provided direct evidence that human endothelial cells are capable of producing biologically active quantities of cAMP-elevating prostaglandins sufficient to induce stoichiometric cAMP-mediated protein phosphorylation in human platelets. VASP-phosphorylation induced by PG-I2 and PG-E1 was completely reversible after removal of the prostaglandins whereas this was only partially the case with Iloprost. In addition, evidence is presented that the prostaglandin-regulated adenylate cyclase system but not the cAMP-mediated protein phosphorylation desensitizes in human platelets after prolonged treatment with cAMP-elevating prostaglandins. VASP phosphorylation is proposed as a marker for quantitating aspects of vessel wall-platelet interaction.
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PMID:Comparison of vasodilatory prostaglandins with respect to cAMP-mediated phosphorylation of a target substrate in intact human platelets. 171 58

Increased platelet reactivity has been suggested in the pathogenesis of both arteriosclerosis and diabetic microangiopathy. Therefore, platelet function and platelet enzyme activities were assessed in a large group of 357 diabetics (256 patients with IDDM, aged 16-49 and 101 patients with NIDDM, aged 50-78) and 163 matched controls, and related to photographically documented retinopathy (Rd) and to peripheral vascular disease (PVD) as well as to plasma levels of von Willebrand factor (VIII R:Ag) as an indicator of endothelial damage. Patients with IDDM had increased platelet aggregation (PA, expressed as microM ADP threshold concentration) before Rd was detectable in comparison to control subjects (P less than 0.01). PA was further increased in patients with advanced Rd (P less than 0.01), whereas 20 newly diagnosed diabetics with IDDM exhibited normal PA. Patients with minimal Rd did not differ from patients without Rd. Plasma beta-thromboglobulin (reflecting platelet consumption in vivo) was enhanced significantly in patients with Rd only (P less than 0.05), as was malondialdehyde (MDA) production of platelets (as a measure of platelet endoperoxide formation). Factor VIII-related antigen in plasma was already increased in patients without Rd (P less than 0.05), yet more so in patients with Rd (P less than 0.01). Prostacyclin-stimulated adenylate cyclase activity (ACA) of platelets (as an antiaggregatory enzyme system) was twice as high in diabetics with advanced Rd compared with patients without Rd and with controls (P less than 0.01). Significant correlations were found between PA and plasma F VIII R: Hg, MDA production, and ACA of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet enzyme activities in diabetes mellitus in relation to endothelial damage. 608 25

Prostacyclin (PGI2) is the product of arachidonic acid metabolism generated by the vessel wall of all mammalian species studied, including man. Prostacyclin is a potent vasodilator and the most potent inhibitor of platelet aggregation so far described. Prostacyclin inhibits aggregation through stimulation of platelet adenyl cyclase leading to an increase in platelet cyclic AMP. In the vessel wall, the enzyme that synthesizes prostacyclin is concentrated in the endothelial layer. Prostacyclin can also be a circulating hormone released from the pulmonary circulation. Based on these observations we proposed that platelet aggregability in vivo is controlled via a prostacyclin mechanism. The discovery of prostacyclin has given a new insight into arachidonic acid metabolism and has led to a new hypothesis about mechanisms of haemostasis. Reductions in prostacyclin production in several diseases, including atherosclerosis and diabetes, have been described and implicated in the pathophysiology of these diseases. Additionally, since prostacyclin powerfully inhibits platelet aggregation and promotes their disaggregation, this agent could have an important use in the therapy of conditions in which increased platelet aggregation takes place and in which, perhaps, a prostacyclin deficiency exists. Prostacyclin has been used beneficially in humans during extracorporeal circulation procedures such as cardiopulmonary bypass, charcoal haemoperfusion and haemodialysis. Its possible use in other conditions such as peripheral vascular disease or transplant surgery is at present being investigated.
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PMID:Prostacyclin: its biosynthesis, actions and clinical potential. 611 93