8-pCPT-conjugated cyclic AMP analogs exert thromboxane receptor antagonistic properties

Sand, Carsten; Grandoch, Maria; Boergermann, Christof; Weernink, Paschal A. Oude; Mahlke, Yvonne; Schwindenhammer, Benjamin; Weber, Artur‐Aron; Fischer, Jens W.; Jakobs, Karl H.; Schmidt, Martina

doi:10.1160/th09-06-0341

Cited by 13 publications

(3 citation statements)

References 65 publications

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“…Moreover, evidence exists that different chemically modified cAMP analogues modulate specific cellular responses. Recently, a study by Sand and colleagues demonstrated that 8-CPT-conjugated but not bromine-conjugated cAMP analogues act as competitive thromboxane receptor antagonists [30]. …”

Section: Discussionmentioning

confidence: 99%

Effect of cAMP derivates on assembly and maintenance of tight junctions in human umbilical vein endothelial cells

et al. 2010

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BackgroundEndothelial tight and adherens junctions control a variety of physiological processes like adhesion, paracellular transport of solutes or trafficking of activated leukocytes. Formation and maintenance of endothelial junctions largely depend on the microenvironment of the specific vascular bed and on interactions of the endothelium with adjacent cell types. Consequently, primary cultures of endothelial cells often lose their specific junctional pattern and fail to establish tight monolayer in vitro. This is also true for endothelial cells isolated from the vein of human umbilical cords (HUVEC) which are widely used as model for endothelial cell-related studies.ResultsWe here compared the effect of cyclic 3'-5'-adenosine monophosphate (cAMP) and its derivates on formation and stabilization of tight junctions and on alterations in paracellular permeability in HUVEC. We demonstrated by light and confocal laser microscopy that for shorter time periods the sodium salt of 8-bromoadenosine-cAMP (8-Br-cAMP/Na) and for longer incubation periods 8-(4-chlorophenylthio)-cAMP (pCPT-cAMP) exerted the greatest effects of all compounds tested here on formation of continuous tight junction strands in HUVEC. We further demonstrated that although all compounds induced protein kinase A-dependent expression of the tight junction proteins claudin-5 and occludin only pCPT-cAMP slightly enhanced paracellular barrier functions. Moreover, we showed that pCPT-cAMP and 8-Br-cAMP/Na induced expression and membrane translocation of tricellulin.ConclusionspCPT-cAMP and, to a lesser extend, 8-Br-cAMP/Na improved formation of continuous tight junction strands and decreased paracellular permeability in primary HUVEC. We concluded that under these conditions HUVEC represent a feasible in vitro model to study formation and disassembly of endothelial tight junctions and to characterize tight junction-associated proteins

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Section: Discussionmentioning

confidence: 99%

Effect of cAMP derivates on assembly and maintenance of tight junctions in human umbilical vein endothelial cells

et al. 2010

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“…Platelets express a number of different membrane-bound AC isoforms, including AC3, AC6, and AC7 [303, 304]. Provided that cAMP is not broken down by PDE, it activates either PKA [305, 288, 306] or exchange proteins activated by cAMP (Epac) [307, 308]. Platelet PKA exists as a tetramer of two regulatory subunits bound to catalytic subunits, RIα/β-C or RIIβ-C, that are inactive in resting platelets.…”

Section: Resting Platelet G Protein-coupled Receptorsmentioning

confidence: 99%

Platelets and cancer: a casual or causal relationship: revisited

Menter

Tucker

Kopetz

et al. 2014

Cancer Metastasis Rev

277

256

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Human platelets arise as subcellular fragments of megakaryocytes in bone marrow. The physiologic demand, presence of disease such as cancer, or drug effects can regulate the production circulating platelets. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. The most critical biological platelet response is serving as “First Responders” during the wounding process. The exposure of extracellular matrix proteins and intracellular components occurs after wounding. Numerous platelet receptors recognize matrix proteins that trigger platelet activation, adhesion, aggregation, and stabilization. Once activated, platelets change shape and degranulate to release growth factors and bioactive lipids into the blood stream. This cyclic process recruits and aggregates platelets along with thrombogenesis. This process facilitates wound closure or can recognize circulating pathologic bodies. Cancer cell entry into the blood stream triggers platelet-mediated recognition and is amplified by cell surface receptors, cellular products, extracellular factors, and immune cells. In some cases, these interactions suppress immune recognition and elimination of cancer cells or promote arrest at the endothelium, or entrapment in the microvasculature, and survival. This supports survival and spread of cancer cells and the establishment of secondary lesions to serve as important targets for prevention and therapy.

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“…While these examples have found diverse uses as probe molecules, issues remain around debatable selectivity (cyclic nucleotides) and cell permeability (007). Moreover, EPAC-specific cAMP analogues, as well as their cellular metabolites, have been reported to exert off-target effects [106–110]. Other examples include sulphonylurea EPAC2 activators and N -acylsulphonamide EPAC1 activators.…”

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confidence: 99%

Selective small-molecule EPAC activators

Luchowska-Stańska

Morgan

Yarwood

et al. 2019

Biochemical Society Transactions

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The cellular signalling enzymes, EPAC1 and EPAC2, have emerged as key intracellular sensors of the secondary messenger cyclic 3′,5′-adenosine monophosphate (cyclic adenosine monophosphate) alongside protein kinase A. Interest has been galvanised in recent years thanks to the emergence of these species as potential targets for new cardiovascular disease therapies, including vascular inflammation and insulin resistance in vascular endothelial cells. We herein summarise the current state-of-the-art in small-molecule EPAC activity modulators, including cyclic nucleotides, sulphonylureas, and N-acylsulphonamides.

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8-pCPT-conjugated cyclic AMP analogs exert thromboxane receptor antagonistic properties

Cited by 13 publications

References 65 publications

Effect of cAMP derivates on assembly and maintenance of tight junctions in human umbilical vein endothelial cells

Effect of cAMP derivates on assembly and maintenance of tight junctions in human umbilical vein endothelial cells

Platelets and cancer: a casual or causal relationship: revisited

Selective small-molecule EPAC activators

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