6-ketoprostaglandin-f1-alpha and Carotid-Artery-Diseases

Recent studies revealed that inflammation contributes to plaque instability. Cyclo-oxygenase (COX)-2 is one of the key enzymes in plaque inflammation. We examined the relation between a polymorphism in the COX-2 gene and carotid plaque echogenicity in patients with high risk of cerebrovascular disease to evaluate the involvement of COX-2 in plaque instability.. The study comprised 469 individuals with carotid atherosclerotic plaques. We quantified the echogenicity of the largest plaque in each participant by integrated backscatter analysis. The -765G > C variant of the COX-2 gene was genotyped by restriction enzyme fragment length polymorphism analysis. Urinary 6-keto prostaglandin F(1)(alpha) levels and flow-mediated dilation were measured in 25 participants from the -765GC genotype group and 25 matched participants from the -765GG genotype group.. The carotid plaque echogenicity in the variant genotype group (n = 44) was lower than that in the -765GG genotype group (n = 425, p = 0.017). The association remained significant when we controlled for atherosclerotic risk factors, plaque thickness and serum levels of interleukin-6 (p = 0.027). The level of urinary 6-keto prostaglandin F(1)(alpha) and flow-mediated dilation in the variant genotype group was significantly lower than that in the -765GG genotype group.. The -765G > C variant of COX-2 was associated with reduced carotid plaque echogenicity in Japanese. Diminished COX-2 activity in the endothelium may contribute to plaque instability.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Atherosclerosis; Carotid Artery Diseases; Cyclooxygenase 2; Diabetes Complications; DNA; Dyslipidemias; Female; Genetic Variation; Genotype; Humans; Japan; Male; Middle Aged; Promoter Regions, Genetic; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Smoking; Ultrasonography

Hyaluronic acid (HA) is a prominent constituent of the extracellular matrix of atherosclerotic vascular lesions in humans known to modulate vascular smooth muscle phenotype. The regulation of HA synthesis by vasodilatory prostaglandins was analyzed in human arterial smooth muscle cells (SMCs). The prostacyclin analogue, iloprost (100 nmol/L), markedly increased pericellular formation of HA coats and HA secretion into the cell culture medium in human arterial SMCs (8.7+/-1.6-fold). Expression of HA synthase 2 (HAS2) was determined by semiquantitative RT-PCR and found to be strongly upregulated at concentrations of iloprost between 1 and 100 nmol/L after 3 hours. Furthermore, endogenous cyclooxygenase-2 (COX2) activity was required for basal expression of HAS2 mRNA in SMCs in vitro. Total HA secretion in response to iloprost was markedly decreased by RNA interference (RNAi), specific for HAS2. In addition, siRNA targeting HAS2 strongly increased the spreading of human SMCs compared with mock-transfected cells. HAS2 mRNA levels were also stimulated by a selective prostacyclin receptor (IP) agonist, cicaprost (10 nmol/L), prostaglandin E(2) (10 nmol/L), and the EP(2) receptor agonist, butaprost (1 micromol/L). Induction of HAS2 mRNA and HA synthesis by prostaglandins was mimicked by stable cAMP analogues and forskolin. In human atherectomy specimens from the internal carotid artery, HA deposits and COX2 expression colocalized frequently. In addition, strong EP(2) receptor expression was detected in SMCs in HA-rich areas. Therefore, upregulation of HAS2 expression via EP(2) and IP receptors might contribute to the accumulation of HA during human atherosclerosis, thereby mediating proatherosclerotic functions of COX2.

Topics: 6-Ketoprostaglandin F1 alpha; Acetophenones; Alprostadil; Arteriosclerosis; Becaplermin; Benzopyrans; Bucladesine; Carotid Artery Diseases; Carotid Artery, Internal; Cells, Cultured; Colforsin; Cyclic AMP; Cyclooxygenase 2; Enzyme Induction; Epoprostenol; Extracellular Matrix; Glucuronosyltransferase; Humans; Hyaluronan Synthases; Hyaluronic Acid; Iloprost; Indoles; Isoenzymes; Isoquinolines; Macrophages; Maleimides; Membrane Proteins; Muscle Cells; Muscle, Smooth, Vascular; Pertussis Toxin; Platelet-Derived Growth Factor; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-sis; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; RNA, Messenger; RNA, Small Interfering; Sulfonamides; Vasodilator Agents

The mechanism by which atherosclerotic disease is induced by cigarette smoking has not yet been identified unequivocally. Chronic cigarette smoking and the generation of vasoactive prostanoids and the size of carotid atherosclerotic plaques were studied in nine pairs of identical male twins discordant for smoking for over 20 years. The urinary excretion of 2,3-dinor-thromboxane B2 (thromboxane B2 metabolite) of the smoking twin was significantly higher (on average 1.8 times higher) in every pair and that of 2,3-dinor-6-keto-prostaglandin F1 alpha (prostacyclin metabolite) was significantly higher (on average 1.3 times higher) in eight of the nine pairs. The ratio of excretion of these metabolites was significantly higher, being 4.0 (95% confidence interval 2.7 to 5.4) among the smokers compared with 2.9 (2.1 to 3.8) among the non-smokers, thus favouring a mechanism of vasoconstriction. Excretion of the thromboxane B2 metabolite was related to the urinary concentrations of nicotine metabolites. Atherosclerotic plaques detected by ultrasonography in the carotid arteries were significantly larger among smokers but did not correlate with the urinary excretion of prostacyclin and thromboxane B2 metabolites or intensity of smoking. Smoking was concluded to induce activation of platelets by an effect mediated by nicotine. The increased prostacyclin production, on the other hand, suggested a compensatory mechanism for the general vasoconstrictive properties of cigarette smoking.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Carotid Artery Diseases; Cotinine; Diseases in Twins; Humans; Male; Middle Aged; Smoking; Thromboxane B2; Twins; Twins, Monozygotic; Ultrasonography

Imbalance between the two arachidonic acid metabolites, prostacyclin (PGI2) and thromboxane A2 (TXA2), is thought to be at least in part responsible for the development of cerebral vasospasm following aneurysm rupture. In 12 patients with subarachnoid hemorrhage the pre- and postoperative serum and CSF levels of PGI2 and TXA2 were measured as a function of their stable hydrolysis products, 6-Keto-PGF1 alpha (PGI2) and thromboxane B2 (TXA2), with a highly specific radioimmunoassay. Serum levels of both metabolites were elevated in half of the patients, but no correlation to the clinical course could be found. However, TXB2 concentration in the CSF was significantly increased preoperatively with close correlation to the amount of intracisternal blood, as detected by CT scan. Furthermore, it could be demonstrated that the postoperative course of the TXB2 concentrations in the CSF reflects the clinical course in such a way that a characteristic secondary rise of TXB2, concentration postoperatively is closely related to the occurrence of cerebral vasospasm and clinical deterioration. The conclusion is drawn that measurement of arachidonic acid metabolites in the CSF may provide important information concerning the pathophysiological events following subarachnoid hemorrhage, especially with regard to incipient cerebral vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Blood-Brain Barrier; Carotid Artery Diseases; Carotid Artery, Internal; Epoprostenol; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Rupture, Spontaneous; Subarachnoid Hemorrhage; Thromboxane A2; Thromboxane B2

Cisternal and lumbar cerebrospinal fluid obtained some days following a subarachnoid haemorrhage contains abnormally large quantities of various prostanoids; some may be partly the result of abnormal production by the cerebral arteries. The extra-arterial and intra-arterial production of 6 oxo PGF1 alpha (prostacyclin metabolite), PGE2, PGF2 alpha and TXB2 were measured in perfused rabbit common carotid arteries taken both from normal rabbits and from rabbits in which the arteries had been ensheathed by blood clot in vivo for 7 days using two techniques. Prostaglandin production by control arteries was highest during the first hour of perfusion but declined or increased marginally (PGE2) during the succeeding three hours. Arteries exposed to a periarterial haematoma for 7 days produced prostaglandins at a high rate throughout the 4 hours of study, and there was a progressive and marked increase in PGE2 production. The disproportionate increase in the cerebral vasoconstrictor PGE2 may reflect the inflammatory response which occurred in the adventitia of the vessels. Increased prostanoid production by cerebral arteries probably does contribute to the increased levels in CSF after subarachnoid haemorrhage.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Carotid Arteries; Carotid Artery Diseases; Dinoprost; Dinoprostone; Eicosanoic Acids; Endothelium; Hematoma; Indomethacin; Prostaglandins E; Prostaglandins F; Rabbits; Subarachnoid Hemorrhage; Thromboxane B2; Vasoconstriction