Arachidonate metabolism in vascular disorders.

Majerus, Philip W.

doi:10.1172/jci111110

Cited by 226 publications

(94 citation statements)

References 39 publications

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“…46 The ability of PAF to activate platelets and neutrophils suggests that this biosynthetic capability may be important in the interaction of endothelium with circulating blood cells and perhaps with other adjacent cells as well. The ability of stimulated endothelial cells to produce PAF, a platelet activator, and PG12, a potent inhibitor of platelet activity,27 45 indicates the potential for the endothelium to regulate the interaction between the two cells directly ( figure 5). This may be important in vascular homeostasis, since platelets are required to maintain endothelial integrity.…”

Section: Discussionmentioning

confidence: 99%

Production of platelet-activating factor by human vascular endothelial cells: evidence for a requirement for specific agonists and modulation by prostacyclin.

Zimmerman¹,

1985

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Primary cultures of confluent endothelial cells derived from human umbilical veins produce platelet-activating factor (PAF) (l -alkyl-2-acetyl-sn-glycero-3-phosphocholine) when This indicates that the synthesis of PAF by cultured human endothelial cells is a response to specific agonists and is not an unregulated event that occurs as a result of nonspecific cellular perturbation. The PAF produced by thrombin-treated endothelial cells is a potent stimulus for platelet activation, as assayed by the aggregation of human platelets in autologous plasma. The production of PAF by endothelial monolayers is attenuated by prostacyclin, another product of stimulated endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Production of platelet-activating factor by human vascular endothelial cells: evidence for a requirement for specific agonists and modulation by prostacyclin.

Zimmerman¹,

1985

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“…9 The opposite actions of PGI2 and TXA2 on the vasculature and platelets are well known, and their balance is critical in the development of various thrombotic diseases, including acute myocardial infarction. 10 Both PGI2 and TXA2 are expressed in heart tissue; PGI2 and its analog have been reported to exert beneficial effects on cardiac ischemic injury, 11 whereas TXA2 is involved in vascular atherosclerosis and has pro-inflammatory characteristics. Therefore, we hypothesized that TXA2 may be the major eicosanoid that mediates iron-overload cardiomyopathy.…”

Section: Assay For Luciferase Activitymentioning

confidence: 99%

Thromboxane A<sub>2</sub> Mediates Iron-Overload Cardiomyopathy in Mice Through Calcineurin-Nuclear Factor of Activated T Cells Signaling Pathway

Lin

Lian

et al. 2013

Circ J

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Background: Recent studies demonstrated that iron overload could enhance the production of arachidonic acid and prostanoid, suggesting a causal connection between these signals and iron-overload cardiomyopathy. However, information regarding the downstream signaling is limited. Because thromboxane A2 (TXA2) and prostacyclin are the 2 major prostanoids in the cardiovascular system, and TXA2 plays a major role in vascular atherosclerosis and has pro-inflammatory characteristics, we intended to elucidate the role of TXA2 in iron-overload cardiomyopathy. Methods and Results:A 4-week iron loading protocol was instituted for both TXAS gene-deleted (TXAS −/− ) mice and wild-type (WT) mice, with less severe cardiac fibrosis and preserved normal left ventricular contraction in the TXAS −/− mice. Inflammatory profiles, including MCP-1, TNF-α, IL-6, ICAM-1, and myeloperoxidase activity were also lower in the TXAS −/− as compared with WT littermates. TXAS supplement to the iron-injured TXAS −/− mice re-aggravated cardiac inflammation. Using a TXA2 analog, U46619, for NFAT reporter luciferase activity on cardiomyoctes, and intraperitonal injection of U46619 into nuclear factor of activated T cells (NFAT)-luciferase transgenic mice demonstrated that U46619 increase NFAT expression, and this expression, as well as TNF-α expression, can be blocked by TXA2 receptor antagonist (SQ29548), NFAT-SiRNA, calcineurin inhibitor, or calcium chelator. Finally, intraperitoneal injection of the TNF-α antibody, infliximab, into iron-injured mice decreased TXAS expression and attenuated cardiac fibrosis.Conclusions: TXA2 mediates iron-overload cardiomyopathy through the TNF-α-associated calcineurin-NFAT signaling pathway. (Circ J 2013; 77: 2586 -2595

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“…They behave like local hormones that act in the vicinity of their production sites [1][2]. Each prostanoid exerts their function by binding to its specific prostanoid receptor.…”

Section: Introductionmentioning

confidence: 99%

Assembling NMR structures for the intracellular loops of the human thromboxane A2 receptor: Implication of the G protein-coupling pocket

Feng

Ruan

2008

Archives of Biochemistry and Biophysics

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It has been reported that the multiple intracellular loops (iLPs) of the thromboxane A 2 receptor (TP) are involved in the receptor G protein coupling. In this study, a high-resolution 2D NMR technique was used to determine the 3D structures of the first, second, and third iLPs of the TP receptor using synthetic peptides constrained into the loop structures. 2D 1H NMR spectra, TOCSY and NOESY were obtained for the two peptides from proton NMR experiments. The NMR data was processed and assigned through the Felix 2000 program. Standard methods were used to acquire sequencespecific assignments. Structure calculations were processed through DGII and NMR refinement programs within the Insight II program. We were able to calculate and use the NOE constraints to obtain the superimposed structure of ten structures for each iLP peptide. The NMR-determined structures of the iLP peptides were used to refine a homology model of the TP receptor. A 3D Gprotein binding cavity, formed by the three intracellular loops, was predicted by the docking of the C-terminal domain of the Gαq. Based on the structural model and the previous mutagenesis, the residues in the TP intracellular loops (R130, R60, C223, F138) and in the Gαq (L360, V361, E358, Y359), which are important for interaction of TP with the G protein, were further highlighted. These results reveal the possibly important molecular mechanisms in TP receptor signaling and provide structural information to characterize other prostanoid receptor signalings.

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Arachidonate metabolism in vascular disorders.

Cited by 226 publications

References 39 publications

Production of platelet-activating factor by human vascular endothelial cells: evidence for a requirement for specific agonists and modulation by prostacyclin.

Production of platelet-activating factor by human vascular endothelial cells: evidence for a requirement for specific agonists and modulation by prostacyclin.

Thromboxane A<sub>2</sub> Mediates Iron-Overload Cardiomyopathy in Mice Through Calcineurin-Nuclear Factor of Activated T Cells Signaling Pathway

Assembling NMR structures for the intracellular loops of the human thromboxane A2 receptor: Implication of the G protein-coupling pocket

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