Prostacyclin, atherothrombosis, and cardiovascular disease
ABSTRACT Prostacyclin (PGI(2)) is a major product of COX-2 catalyzed metabolism of arachidonic acid in the endothelium. Recent studies have demonstrated that PGI(2) protects against atherothrombosis. The prostacyclin receptor knockout mice exhibit increased atherosclerosis, enhanced thrombosis, and enhanced proliferative response to carotid vascular injury with increased intima to media ratios [1-3]. Moreover, the recent withdrawal of rofecoxib (Vioxx) due to increased cardiovascular events further supports the critical role of prostacyclin in inhibiting atherothrombosis in humans. Such studies have paralleled intense chemical biology studies to develop more stable prostacyclin analogues. Indeed a number of these analogues are currently being successfully used for the treatment of pulmonary hypertension. In this review we will summarize the current literature on some principles of prostacyclin analogue development, our current understanding of the receptor, and recent developments which implicate prostacyclin in atherothrombotic protection. More than 68 million Americans suffer from cardiovascular disease, which causes more deaths, disability and economic loss than any other group of diseases. Further clinical investigations of orally stable prostacyclin analogues for treatment of cardiovascular diseases other than pulmonary hypertension may now be warranted.
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ABSTRACT: Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 18-02-2008 Peer reviewed
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ABSTRACT: Pretreatment using celecoxib, a cyclooxygenase (COX) 2 inhibitor, or indomethacin, a nonselective COX inhibitor, reduced lypopolyssaccharide (LPS)-induced leukocyte migration to the rat peritoneal cavity. The effect of celecoxib (12 mg/kg) or indomethacin (2 mg/kg) on neutrophil chemotaxis induced by formyl-methionyl-leucyl-phenylalanine (FMLP) in an in vitro chemotactic assay (Boyden chamber) was investigated. Celecoxib and indomethacin inhibited chemotaxis induced by FMLP (Control=26.6+/-1.45, Celecoxib=12.8+/-3.04, Indomethacin=6.26+/-2.19 cells/field). When observed under intravital microscopy, a mouse cremaster preparation was used to assess the microvasculature to further investigate which step of cell recruitment was affected by these drugs. Celecoxib and indomethacin inhibited leukocyte migration induced by 0.05 microg/kg LPS injected into the cremaster muscle. However, the effect of celecoxib was associated with reduced cell rolling and adhesion, whereas indomethacin was only effective at inhibiting cell adhesion. Furthermore, SC560 pretreatment (a COX-1 selective inhibitor) of normal or LPS-challenged tissues did not alter leukocyte migration or cell adhesion, but it did enhance leukocyte rolling activity in both cases. Taken together, these results indicate that: 1) COX-1 activity is mainly related to leukocyte traffic under physiological conditions, and 2) COX-2 activity is mainly related to cell traffic under inflammatory conditions in vascular beds, suggesting a possible effect of selective COX-2 inhibitors on the expression of adhesion molecules.European Journal of Pharmacology 10/2008; 598(1-3):118-22. DOI:10.1016/j.ejphar.2008.08.037 · 2.68 Impact Factor
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ABSTRACT: The aim of the present study was to determine the impact of increased consumption of phytosterols or phytostanols on blood pressure and renal blood pressure regulatory gene expression in stroke-prone spontaneously hypertensive (SHRSP) and normotensive Wistar-Kyoto (WKY) inbred rats. SHRSP and WKY inbred rats (10/group) were fed a control diet or a diet supplemented with phytosterols or phytostanols (2.0 g/kg diet). After 5 weeks, SHRSP rats demonstrated higher systolic and diastolic blood pressures than WKY inbred rats. SHRSP rats that consumed the phytosterol or phytostanol supplemental diets displayed a 2- or 3-fold respective increase in the diastolic blood pressure than those that consumed the control diet. Angiotensinogen (Agt), angiotensin I-converting enzyme 1 (Ace1), nitric oxide synthase (Nos) 1, Nos3, cyclooxygenase 2 (Cox2) and THUMP domain containing 1 were expressed at higher levels in SHRSP compared with WKY inbred rats. Renin and angiotensin II receptor type 1a were expressed at lower levels in SHRSP than WKY inbred rats. Phytostanol supplementation up-regulated the expression of Ace1 and Nos3 in SHRSP rats. Phytosterol supplementation increased the mRNA levels of Nos1 and spondin 1 (Spon1) in SHRSP and WKY inbred rats. Cox2 mRNA levels were elevated in both phytosterol- and phytostanol-supplemented SHRSP and WKY inbred rats. Therefore, the increased blood pressure in SHRSP rats may be partly due to altered renal expression of blood pressure regulatory genes. Specifically, up-regulation of Ace1, Nos1, Nos3, Cox2 and Spon1 were associated with the increased diastolic blood pressure observed in phytosterol- or phytostanol-supplemented SHRSP rats.The British journal of nutrition 12/2008; 102(1):93-101. DOI:10.1017/S0007114508137904 · 3.34 Impact Factor