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Prostacyclin: an inflammatory paradox.

Stitham J, Midgett C, Martin KA, Hwa J - Front Pharmacol (2011)

Bottom Line: In recent years, prostacyclin (PGI(2)) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells.In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI(2)) also plays an important role as an inflammatory mediator.The emerging role of prostacyclin (PGI(2)) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments.

View Article: PubMed Central - PubMed

Affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Yale University New Haven, CT, USA.

ABSTRACT
Prostacyclin (PGI(2)) is a member of the prostaglandin family of bioactive lipids. Its best-characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin (PGI(2)) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI(2)) also plays an important role as an inflammatory mediator. In this review, we focus on the contribution of prostacyclin (PGI(2)) as both a pathophysiological mediator and therapeutic agent in three major inflammatory-mediated disease processes, namely rheumatoid arthritis, where it promotes disease progression ("pro-inflammatory"), along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression ("anti-inflammatory"). The emerging role of prostacyclin (PGI(2)) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments.

No MeSH data available.


Related in: MedlinePlus

Prostanoid biosynthesis pathway. The enzyme phospholipase A2 (PLA2) hydrolyzes arachidonic acid (AA) from the phospholipids of the extracellular membrane. Arachidonic acid is modified by the cyclooxygenase (COX) enzymes (COX-1 and COX-2) to form the intermediate precursor prostaglandin G2 (PGG2) via the addition of two oxygen (O2) molecules. Prostaglandin H2 (PGH2) is subsequently formed by the actions of peroxidase enzyme, which releases a single oxygen (O2) molecule. As shown, all prostanoids are derived from the parent compound PGH2 and are formed via their respective synthase enzymes, namely prostaglandin I2 synthase (PGIS), prostaglandin E2 synthase (PGES-1), prostaglandin D2 synthase (PGDS), prostaglandin F2α synthase (PGES-2), and thromboxane A2 synthase (TBXAS-1).
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Figure 1: Prostanoid biosynthesis pathway. The enzyme phospholipase A2 (PLA2) hydrolyzes arachidonic acid (AA) from the phospholipids of the extracellular membrane. Arachidonic acid is modified by the cyclooxygenase (COX) enzymes (COX-1 and COX-2) to form the intermediate precursor prostaglandin G2 (PGG2) via the addition of two oxygen (O2) molecules. Prostaglandin H2 (PGH2) is subsequently formed by the actions of peroxidase enzyme, which releases a single oxygen (O2) molecule. As shown, all prostanoids are derived from the parent compound PGH2 and are formed via their respective synthase enzymes, namely prostaglandin I2 synthase (PGIS), prostaglandin E2 synthase (PGES-1), prostaglandin D2 synthase (PGDS), prostaglandin F2α synthase (PGES-2), and thromboxane A2 synthase (TBXAS-1).

Mentions: Prostacyclin (PGI2) is a member of the prostaglandin family of bioactive lipids, and is a derivative of the 20-carbon, omega-6 fatty acid, arachidonic acid (AA or 5,8,11,14-eicosatetraenoic acid). Both cyclooxygenase enzymes (COX-1 and COX-2) convert AA into the prostaglandin precursor PGH2, which is subsequently synthesized into prostacyclin (PGI2) via prostacyclin synthase (PGIS; Figure 1). However, the majority of PGI2 produced in vivo, particularly within the systemic and pulmonary vasculature (Moncada et al., 1977; Catella-Lawson et al., 1999; McAdam et al., 1999), and other regions like the synovium (Brodie et al., 1980; Crofford et al., 1994), appears to be derived from COX-2. PGI2 is unstable at physiological pH and, thus, has a very short half-life in vivo (<2 min), rapidly forming the inactive hydration product 6-keto-prostaglandin F1α (6-keto-PGF1α; Lewis and Dollery, 1983; Smyth and FitzGerald, 2002). The actions of PGI2 are mediated through a seven-transmembrane-spanning G-protein coupled receptor (GPCR), referred to as the IP receptor (International Union of Pharmacology nomenclature). The IP receptor is a Class A rhodopsin-like GPCR that couples predominately to the Gs subunit of the heterotrimeric G-protein and mediates intracellular signaling via adenylyl cyclase (AC) activation and cyclic AMP (cAMP) production (Boie et al., 1994). Animal studies have also shown that PGI2 may also signal through alternate Gq- and Gi-related pathways (Lawler et al., 2001), as well as nuclear receptor-mediated pathways, such as the peroxisome proliferator activated receptor gamma (PPARδ) pathway (Lim and Dey, 2002). Stitham et al. (2003) have elucidated the putative binding pocket for the human IP receptor, which has been reported to also accommodate type E prostanoids (i.e., PGE1 and PGE2) in addition to its native ligand PGI2 and its analogs (Boie et al., 1994; Nakagawa et al., 1994). The physiological effects of PGI2 are vast with much remaining to be uncovered. Within the vasculature, PGI2 serves as a potent vasodilator and is the major inhibitory prostanoid in platelet aggregation (Smyth et al., 2009), and has also been shown to inhibit vascular smooth muscle cell (VSMC) proliferation and de-differentiation (Fetalvero et al., 2006, 2007). Within the lungs, PGI2 reduces pulmonary blood pressure as well as bronchial hyper-responsiveness (Idzko et al., 2007). Within the kidneys, PGI2 serves to regulate renal blood flow and glomerular filtration rate, as well as mediates the release of renin (Komhoff et al., 1998). In the nervous system, PGI2 has been shown to elicit nociceptive pain response (Murata et al., 1997).


Prostacyclin: an inflammatory paradox.

Stitham J, Midgett C, Martin KA, Hwa J - Front Pharmacol (2011)

Prostanoid biosynthesis pathway. The enzyme phospholipase A2 (PLA2) hydrolyzes arachidonic acid (AA) from the phospholipids of the extracellular membrane. Arachidonic acid is modified by the cyclooxygenase (COX) enzymes (COX-1 and COX-2) to form the intermediate precursor prostaglandin G2 (PGG2) via the addition of two oxygen (O2) molecules. Prostaglandin H2 (PGH2) is subsequently formed by the actions of peroxidase enzyme, which releases a single oxygen (O2) molecule. As shown, all prostanoids are derived from the parent compound PGH2 and are formed via their respective synthase enzymes, namely prostaglandin I2 synthase (PGIS), prostaglandin E2 synthase (PGES-1), prostaglandin D2 synthase (PGDS), prostaglandin F2α synthase (PGES-2), and thromboxane A2 synthase (TBXAS-1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108482&req=5

Figure 1: Prostanoid biosynthesis pathway. The enzyme phospholipase A2 (PLA2) hydrolyzes arachidonic acid (AA) from the phospholipids of the extracellular membrane. Arachidonic acid is modified by the cyclooxygenase (COX) enzymes (COX-1 and COX-2) to form the intermediate precursor prostaglandin G2 (PGG2) via the addition of two oxygen (O2) molecules. Prostaglandin H2 (PGH2) is subsequently formed by the actions of peroxidase enzyme, which releases a single oxygen (O2) molecule. As shown, all prostanoids are derived from the parent compound PGH2 and are formed via their respective synthase enzymes, namely prostaglandin I2 synthase (PGIS), prostaglandin E2 synthase (PGES-1), prostaglandin D2 synthase (PGDS), prostaglandin F2α synthase (PGES-2), and thromboxane A2 synthase (TBXAS-1).
Mentions: Prostacyclin (PGI2) is a member of the prostaglandin family of bioactive lipids, and is a derivative of the 20-carbon, omega-6 fatty acid, arachidonic acid (AA or 5,8,11,14-eicosatetraenoic acid). Both cyclooxygenase enzymes (COX-1 and COX-2) convert AA into the prostaglandin precursor PGH2, which is subsequently synthesized into prostacyclin (PGI2) via prostacyclin synthase (PGIS; Figure 1). However, the majority of PGI2 produced in vivo, particularly within the systemic and pulmonary vasculature (Moncada et al., 1977; Catella-Lawson et al., 1999; McAdam et al., 1999), and other regions like the synovium (Brodie et al., 1980; Crofford et al., 1994), appears to be derived from COX-2. PGI2 is unstable at physiological pH and, thus, has a very short half-life in vivo (<2 min), rapidly forming the inactive hydration product 6-keto-prostaglandin F1α (6-keto-PGF1α; Lewis and Dollery, 1983; Smyth and FitzGerald, 2002). The actions of PGI2 are mediated through a seven-transmembrane-spanning G-protein coupled receptor (GPCR), referred to as the IP receptor (International Union of Pharmacology nomenclature). The IP receptor is a Class A rhodopsin-like GPCR that couples predominately to the Gs subunit of the heterotrimeric G-protein and mediates intracellular signaling via adenylyl cyclase (AC) activation and cyclic AMP (cAMP) production (Boie et al., 1994). Animal studies have also shown that PGI2 may also signal through alternate Gq- and Gi-related pathways (Lawler et al., 2001), as well as nuclear receptor-mediated pathways, such as the peroxisome proliferator activated receptor gamma (PPARδ) pathway (Lim and Dey, 2002). Stitham et al. (2003) have elucidated the putative binding pocket for the human IP receptor, which has been reported to also accommodate type E prostanoids (i.e., PGE1 and PGE2) in addition to its native ligand PGI2 and its analogs (Boie et al., 1994; Nakagawa et al., 1994). The physiological effects of PGI2 are vast with much remaining to be uncovered. Within the vasculature, PGI2 serves as a potent vasodilator and is the major inhibitory prostanoid in platelet aggregation (Smyth et al., 2009), and has also been shown to inhibit vascular smooth muscle cell (VSMC) proliferation and de-differentiation (Fetalvero et al., 2006, 2007). Within the lungs, PGI2 reduces pulmonary blood pressure as well as bronchial hyper-responsiveness (Idzko et al., 2007). Within the kidneys, PGI2 serves to regulate renal blood flow and glomerular filtration rate, as well as mediates the release of renin (Komhoff et al., 1998). In the nervous system, PGI2 has been shown to elicit nociceptive pain response (Murata et al., 1997).

Bottom Line: In recent years, prostacyclin (PGI(2)) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells.In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI(2)) also plays an important role as an inflammatory mediator.The emerging role of prostacyclin (PGI(2)) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments.

View Article: PubMed Central - PubMed

Affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, Yale University New Haven, CT, USA.

ABSTRACT
Prostacyclin (PGI(2)) is a member of the prostaglandin family of bioactive lipids. Its best-characterized role is in the cardiovascular system, where it is released by vascular endothelial cells, serving as a potent vasodilator and inhibitor of platelet aggregation. In recent years, prostacyclin (PGI(2)) has also been shown to promote differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI(2)) also plays an important role as an inflammatory mediator. In this review, we focus on the contribution of prostacyclin (PGI(2)) as both a pathophysiological mediator and therapeutic agent in three major inflammatory-mediated disease processes, namely rheumatoid arthritis, where it promotes disease progression ("pro-inflammatory"), along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression ("anti-inflammatory"). The emerging role of prostacyclin (PGI(2)) in this context provides new opportunities for understanding the complex molecular basis for inflammatory-related diseases, and insights into the development of current and future anti-inflammatory treatments.

No MeSH data available.


Related in: MedlinePlus