Biology and therapeutic potential of prostacyclin.

Moncada, Salvador

doi:10.1161/01.str.14.2.157

Cited by 106 publications

(41 citation statements)

References 169 publications

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“…The PGI2 Analog Cicaprost Relaxes SM, Increases Rap1 Activity, and Decreases RhoA Activity-Prostacyclin (PGI2) is the main product of arachidonic acid production with strong hypotensive effects and a vasodilator activity toward all vascular beds (40). Such activity is largely mediated by cAMP production (41,42).…”

Section: -Pcpt-2ј-o-me-camp (007)-induced Relaxation Of Force and Rlcmentioning

confidence: 99%

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

Zieba

Artamonov

Jin

et al. 2011

Journal of Biological Chemistry

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This study reports a new mechanism of cAMP mediated relaxation of Ca2+sensitized force, in smooth muscle (SM) through Epac, a GTP exchange factor for the small GTPase Rap1 which results in suppression of RhoA activity. We find that Epac selective cAMP analogue, 8‐pCPT‐2′‐O‐Me‐cAMP (007), significantly reduced agonist‐induced contractile force, in both intact and permeabilized vascular, gut and airway SM. Responses to 007 were independent of PKA and PKG. Activation of Epac resulted in increased Rap1·GTP accompanied by a significant decrease in RhoA activity and reductions in phosphorylation of RLC20 and MLCP. Transcriptional regulation of SM α‐actin and SM22, known to be regulated by RhoA, was also significantly decreased by activation of Epac. Forskolin, the phosphodiesterase inhibitor IBMX and isoproterenol significantly increased Rap1·GTP in rat aortic SM cells. Over‐expression of wild‐type Epac but not dominant negative Epac1R279E increased Rap1 activation after 007 stimulation. LPA‐induced activation of RhoA activity was reduced by treatment with 007 in WT but not Rap1B null fibroblasts. All together, our findings show a novel signaling mechanism whereby activation of Epac via cAMP results in PKA independent, Rap1 dependent Ca2+ desensitization of force in SM.

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Section: -Pcpt-2ј-o-me-camp (007)-induced Relaxation Of Force and Rlcmentioning

confidence: 99%

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

Zieba

Artamonov

Jin

et al. 2011

Journal of Biological Chemistry

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“…An endocrine luteotropic effect of PGI 2 is conceivable by means of counter-current passage (Milvae & Hansel 1980). More locally, in mice in a first line of action, PGI 2 increases endometrial vascular permeability as potent vasoactive agent thus mediating implantation (Moncada 1983). The invasive implantation sites in mice specifically express high levels of PTGIS (Lim et al 1999).…”

Section: Prostaglandins In the Bovine Uterusmentioning

confidence: 99%

Quantitative characterization of prostaglandins in the uterus of early pregnant cattle

Ulbrich¹,

Schülke²,

Groebner³

et al. 2009

Reproduction

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Prostaglandins (PGs) are important regulators of reproductive processes including early embryonic development. We analyzed the most relevant PG in bovine uteri at different preimplantation pregnancy stages when compared with non-pregnant controls. Additionally, endometrium and trophoblast tissues were examined regarding specific enzymes and receptors involved in PG generation and function. Simmental heifers were artificially inseminated or received seminal plasma only. At days 12, 15, or 18, post-estrus uteri were flushed for PG determination by liquid chromatography-tandem mass spectrometry. Endometrium and trophoblast tissues were sampled for RNA extraction and quantitative real-time PCR analysis. At all days and points of time examined, the concentration of 6-keto PGF 1a (stable metabolite of PGI 2 ) was predominant followed by PGF 2a OPGE 2 OPGD 2 zTXB 2 (stable metabolite of TXA 2 ). At days 15 and 18, PG increased from overall low levels at day 12, with a much more pronounced increase during pregnancy. The PGF 2a /PGE 2 ratio was not influenced by status. The highest PG concentration was measured at day 15 with 6-keto PGF 1a (6.4 ng/ml) followed by PGF 2a (1.1 ng/ml) and PGE 2 (0.3 ng/ml). Minor changes in endometrial PG biosynthesis enzymes occurred due to pregnancy. Trophoblasts revealed high transcript abundance of general and specific PG synthases contributing to uterine PG. As PGI 2 and PGF 2a receptors were abundantly expressed by the trophoblast, abundant amounts of PGI 2 and PGF 2a in the uterine lumen point towards an essential role of PG for the developing embryo. High amounts of PG other than PGE 2 in the preimplantation uterus may be essential rather than detrimental for successful reproduction.

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“…These PGs are primarily generated by uterine COX2, as uterine COX1 expression is very low or undetectable during this time (Chakraborty et al 1996). Because PGI 2 is a potent vasoactive agent (Moncada 1983) and participates in vascular permeability changes (Murohara et al 1997;Wheeler-Jones et al 1997), this lipid mediator may be associated with increased localized vascular permeability in the uterus during implantation.…”

Section: Pgi 2 Is the Most Abundant Pg At The Implantation Sitesmentioning

confidence: 99%

Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta

Lim

Gupta

et al. 1999

Genes & Development

559

360

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We have demonstrated previously that cyclo-oxygenase-2 (COX2), the rate-limiting enzyme in the biosynthesis of prostaglandins (PGs), is essential for blastocyst implantation and decidualization. However, the candidate PG(s) that participates in these processes and the mechanism of its action remain undefined. Using COX2-deficient mice and multiple approaches, we demonstrate herein that COX2-derived prostacyclin (PGI 2 ) is the primary PG that is essential for implantation and decidualization. Several lines of evidence suggest that the effects of PGI 2 are mediated by its activation of the nuclear hormone receptor PPAR␦, demonstrating the first reported biologic function of this receptor signaling pathway.

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Biology and therapeutic potential of prostacyclin.

Cited by 106 publications

References 169 publications

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

The cAMP-responsive Rap1 Guanine Nucleotide Exchange Factor, Epac, Induces Smooth Muscle Relaxation by Down-regulation of RhoA Activity

Quantitative characterization of prostaglandins in the uterus of early pregnant cattle

Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta

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