Prostacyclin: A Vascular Mediator

Vane, John R.; Corin, Robert E.

doi:10.1016/s1078-5884(03)00385-x

Cited by 105 publications

(66 citation statements)

References 74 publications

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“…P rostaglandin I 2 (prostacyclin; epoprostenol) is an oxygenated metabolite of arachidonic acid formed enzymatically by the sequential activities of cyclooxygenase and PGI synthase enzymes (1). It is produced constitutively by vascular endothelial and smooth muscle cells (2) and is induced under inflammatory conditions in vascular cells (3) and macrophages (4).…”

Section: Synthetic Prostacyclin Analogs Differentially Regulate Macromentioning

confidence: 99%

“…In light of its potent vasodilatory properties, PGI 2 has been exploited as a pharmacological agent in the treatment of vasoconstrictive/ischemic diseases such as peripheral vascular arterial occlusive disease, cerebrovascular ischemia, and pulmonary arterial hypertension (PAH) (1). Although native PGI 2 is inherently unstable at room temperature with a t 1/2 of seconds to minutes (6), continuous infusions of a highly alkaline solution (pH 10.2 to 10.8) are approved by the U.S. Food and Drug Administration (FDA) in the treatment of PAH.…”

Section: Synthetic Prostacyclin Analogs Differentially Regulate Macromentioning

confidence: 99%

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Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Aronoff

Peres

Serezani

et al. 2007

The Journal of Immunology

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PGI2 (prostacyclin) is a lipid mediator with vasodilatory and antithrombotic effects used in the treatment of vasoconstrictive/ischemic diseases including pulmonary artery hypertension. However, emerging research supports a role for PGs, including PGI2, in the regulation of both innate and acquired immunity. As PGI2 is unstable, we sought to define the effects of various PGI2 analogs on resident alveolar macrophage (AM) and peritoneal macrophage (PM) innate immune functions. The effects of iloprost, carbaprostacyclin, and treprostinil on the regulation of phagocytosis, bacterial killing, and inflammatory mediator production were determined in both macrophage populations from rats. Iloprost failed to suppress AM functions to the same degree that it did in PMs, a characteristic shared by carbaprostacyclin. This difference reflected greater expression of the Gαs protein-coupled I prostanoid receptor and greater cAMP generation in PMs than AMs. Treprostinil inhibited phagocytosis, bacterial killing, and cytokine generation in AMs to a much greater degree than the other PGI2 analogs and more closely resembled the effects of PGE2. Studies with the E prostanoid (EP) 2 receptor antagonist AH-6809 and EP2-null macrophages indicated that this was due in part to the previously unknown ability of treprostinil to stimulate the EP2 receptor. The present investigation for the first time identifies differences in immunoregulatory properties of clinically administered PGI2 analogs. These studies are the first to explore the capacity of PGI2 to regulate bacterial killing and phagocytosis in macrophages, and our findings may hold important consequences regarding the risk of infection for patients receiving such agents.

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Section: Synthetic Prostacyclin Analogs Differentially Regulate Macromentioning

confidence: 99%

Section: Synthetic Prostacyclin Analogs Differentially Regulate Macromentioning

confidence: 99%

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Aronoff

Peres

Serezani

et al. 2007

The Journal of Immunology

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“…COX exist as two isoforms; COX-1 is constitutively expressed whereas COX-2 is up-regulated by various proinflammatory mediators, such as lipopolysaccharide, growth factors, cytokines and apolipoproteins [16]. The major eicosanoids produced by the activation of COX-2 in endothelial cells are prostacyclin (PGI 2 ) and prostaglandin E2 (PGE 2 ) [17]. The PGI 2 signaling cascade is dependent upon activation of its prostacyclin receptor (IP), which is generally associated with a G stimulatory protein coupled receptor [18].…”

Section: Introductionmentioning

confidence: 99%

Structure–function properties of the apoE-dependent COX-2 pathway in vascular smooth muscle cells

et al. 2008

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Apolipoprotein (apoE) E is a multifunctional protein that plays a critical role in atherogenesis, in part by regulating the intimal proliferation of vascular smooth muscle cells. Recently, a novel cyclooxygenase (COX)-2 pathway was shown to contribute to the anti-proliferative action of human apoE3 in vascular smooth muscle cells (VSMC). Here, we provide insight into the structure-function properties by which apoE mediates these effects. ApoE3 is most effective in promoting COX-2 expression as a lipid-free protein and is less active after lipidation. Alterations in the stability of the helix-bundle N-terminal domain of apoE that contains the binding site for the low density lipoprotein (LDL) receptor and heparin do not affect the up-regulation of the COX-2 pathway. In addition, the apoE2, 3, and 4 isoforms are all capable of up-regulating the COX-2 pathway. Finally, the effect of apoE on COX-2 was found to be independent of expression on the VSMC surface of the LDL receptor and heparan sulfate proteoglycans (HSPG). In summary, our data indicates that apoE, particularly in the lipid-free state, can up-regulate COX-2 in murine vascular smooth muscle cells apparently independently of binding to the LDLR, LRP or HSPG.

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“…PGI 2 mediates its effects through a G s protein-coupled receptor (IP), which is located on vascular smooth muscle cells (VSMCs). 1 Stimulation of IP by PGI 2 leads to an increase in cAMP, which likely mediates relaxation of VSMCs. 2 Vasodilation is a major symptom of infection and inflammation, occurring systematically during sepsis.…”

mentioning

confidence: 99%

Activation of the PGI ₂ /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock

et al. 2008

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Abstract-Prostacyclin levels are increased in septic patients and several animal models of septic shock, and selective inhibition of cyclooxygenase-2 improved cardiovascular dysfunction in rats treated with lipopolysaccharide (LPS).Here, we examine the specific role of prostacyclin and of the receptor for prostacyclin (IP) in the development of LPS-induced circulatory failure. Intravenous injection of LPS (10 mg/kg) into male Sprague-Dawley rats caused a strong increase in plasma prostacyclin levels, which was paralleled by a decrease in blood pressure and an increase in heart rate. Moreover, LPS injection increased the mRNA expression of the IP receptor in the heart, aorta, lung, liver, adrenal glands, and kidneys. Cotreatment with the IP antagonist CAY-10441 (1, 10, 30, and 100 mg/kg) dosedependently moderated the LPS-induced changes in mean arterial blood pressure, heart rate, cardiac output, and systemic vascular resistance Key Words: prostacyclin Ⅲ LPS Ⅲ CAY-10441 Ⅲ blood pressure Ⅲ sepsis P rostacyclin (PGI 2 ) is a major product of the arachidonic acid metabolism formed in the vascular endothelium by the action of the enzymes cyclooxygenase (COX) and prostacyclin synthase (PGIS). PGI 2 mediates its effects through a G s protein-coupled receptor (IP), which is located on vascular smooth muscle cells (VSMCs). 1 Stimulation of IP by PGI 2 leads to an increase in cAMP, which likely mediates relaxation of VSMCs. 2 Vasodilation is a major symptom of infection and inflammation, occurring systematically during sepsis. In the past years, it became obvious that an increased expression of the inducible isoform of NO synthase contributes fundamentally to septic shock. However, in contrast to the effect of the inducible isoform of NO synthase inhibitory drugs on hypotension in shock, 3,4 administration of lipopolysaccharide (LPS) still causes hypotension in the inducible isoform of NO synthase-deficient mice, 5,6 suggesting that NO is not the only mediator of LPS-induced hypotension.Increased levels of PGI 2 have been reported in patients under septic shock and in animals treated with LPS or proinflammatory cytokines. 7-9 Because PGI 2 is a potent vasodilator, one may assume that PGI 2 could be involved in the development of septic shock. Recent evidence suggests that the inducible isoform of COX, COX-2, is the main responsible enzyme for the increased production of PGI 2 in VSMCs. 10,11 In line with this, it has been shown that inhibition of COX-2 attenuates the fall in blood pressure or improves vascular endothelial dysfunction in endotoxemic animals. 12,13 Therefore, we hypothesized that the PGI 2 /IP system could especially contribute to the development of LPS-induced septic shock.

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Prostacyclin: A Vascular Mediator

Cited by 105 publications

References 74 publications

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Structure–function properties of the apoE-dependent COX-2 pathway in vascular smooth muscle cells

Activation of the PGI ₂ /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock

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Prostacyclin: A Vascular Mediator

Cited by 105 publications

References 74 publications

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

Structure–function properties of the apoE-dependent COX-2 pathway in vascular smooth muscle cells

Activation of the PGI 2 /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock

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Activation of the PGI ₂ /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock