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.
- SourceAvailable from: Chenguang Niu[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Dysfunctional high-density lipoprotein (HDL) may have pro-inflammatory effects on the endothelial cells,which causes atherosclerosis in type 2 diabetes mellitus (T2DM). HDL is a major carrier of sphingosine-1-phosphate (S1P) in plasma while S1P exhibits multiple biological activities. However, potential role of HDL and S1P in T2DM remains unexplored. We hypothesized that diabetic HDL with higher contents of S1P exerts beneficial effects on the vascular system. METHODS: Subjects with T2DM with or without proved large arteries atherosclerosis and normal controls (n=15 for each group) were recruited in the present study. HDL was isolated from the subjects by ultracentrifugation. The levels of HDL-associated S1P were determined by UPLC-MS/MS. The protective function of diabetic HDL and S1P was evaluated by measuring cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release by human umbilical vein endothelial cells (HUVECs) using western blot and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: The S1P levels in isolated HDL were significantly increased in T2DM subjects compared with controls (235.6 +/- 13.4 vs 195.0 +/- 6.4 ng/mg, P< 0.05). The diabetic HDL exerted greater protective effects on inducing COX-2 expression and PGI-2 release by HUVECs than those of control HDL (p < 0.05, p < 0.01, respectively). Pertussis toxin, a common inhibitor of G-couple protein receptors, and VPC 23019, an antagonist of S1P receptor 1 and 3 significantly attenuated HDL-induced COX-2 expression and PGI-2 release. CONCLUSIONS: Diabetic HDL carries higher level of S1P compared with normal HDL, which has the potential to contribute to protective effects on endothelial cells by inducing COX-2 expression and PGI-2 release. These findings provide a new insight of S1P function in T2DM patients, possibly leading to a new therapeutic target.Cardiovascular Diabetology 01/2013; 12(1):27. · 4.21 Impact Factor
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ABSTRACT: Currently, pharmacogenetic studies are at an impasse as the low prevalence (<2%) of most variants hinder their pharmacogenetic analysis with population sizes often inadequate for sufficiently powered studies. Grouping rare mutations by functional phenotype rather than mutation site can potentially increase sample size. Using human population-based studies (n = 1,761) to search for dysfunctional human prostacyclin receptor (hIP) variants, we recently discovered 18 non-synonymous mutations, all with frequencies less than 2% in our study cohort. Eight of the 18 had defects in binding, activation, and/or protein stability/folding. Mutations (M113T, L104R, and R279C) in three highly conserved positions demonstrated severe misfolding manifested by impaired binding and activation of cell surface receptors. To assess for association with coronary artery disease, we performed a case-control study comparing coronary angiographic results from patients with reduced cAMP production arising from the non-synonymous mutations (n = 23) with patients with non-synonymous mutations that had no reduction in cAMP (n = 17). Major coronary artery obstruction was significantly increased in the dysfunctional mutation group in comparison with the silent mutations. We then compared the 23 dysfunctional receptor patients with 69 age- and risk factor-matched controls (1:3). This verified the significantly increased coronary disease in the non-synonymous dysfunctional variant cohort. This study demonstrates the potential utility of in vitro functional characterization in predicting clinical phenotypes and represents the most comprehensive characterization of human prostacyclin receptor genetic variants to date.Journal of Biological Chemistry 12/2010; 286(9):7060-9. · 4.65 Impact Factor
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ABSTRACT: Prostacyclin (PGI(2)) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A(2), cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI(2) is produced by endothelial cells and influences many cardiovascular processes. PGI(2) acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI(2) analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI(2)/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca(2+)](i), and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI(2) intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI(2) counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A(2) (TXA(2)), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI(2)/TXA(2) balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI(2)/TXA(2) ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI(2) activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI(2) analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA(2) synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI(2) analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI(2) metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI(2)-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.Pharmacological reviews 06/2012; 64(3):540-82. · 17.00 Impact Factor