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Molecular Pharmacology

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Research ArticleArticle

Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca2+ and Differentially Interact with Platelet-Type 12-Lipoxygenase

Daniel Poeckel, Lars Tausch, Nicole Kather, Johann Jauch and Oliver Werz
Molecular Pharmacology September 2006, 70 (3) 1071-1078; DOI: https://doi.org/10.1124/mol.106.024836
Daniel Poeckel
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Lars Tausch
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Nicole Kather
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Johann Jauch
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Oliver Werz
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Abstract

Boswellic acids inhibit the transformation of arachidonic acid to leukotrienes via 5-lipoxygenase but can also enhance the liberation of arachidonic acid in human leukocytes and platelets. Using human platelets, we explored the molecular mechanisms underlying the boswellic acid-induced release of arachidonic acid and the subsequent metabolism by platelet-type 12-li-poxygenase (p12-LO). Both β-boswellic acid and 3-O-acetyl-11-keto-boswellic acid (AKBA) markedly enhanced the release of arachidonic acid via cytosolic phospholipase A2 (cPLA2), whereas for generation of 12-hydro(pero)xyeicosatetraenoic acid [12-H(P)ETE], AKBA was less potent than β-boswellic acid and was without effect at higher concentrations (≥30 μM). In contrast to thrombin, β-boswellic acid-induced release of ara-chidonic acid and formation of 12-H(P)ETE was more rapid and occurred in the absence of Ca2+. The Ca2+-independent release of arachidonic acid and 12-H(P)ETE production elicited by β-boswellic acid was not affected by pharmacological inhibitors of signaling molecules relevant for agonist-induced arachidonic acid liberation and metabolism. It is noteworthy that in cell-free assays, β-boswellic acid increased p12-LO catalysis approximately 2-fold in the absence but not in the presence of Ca2+, whereas AKBA inhibited p12-LO activity. No direct modulatory effects of boswellic acids on cPLA2 activity in cell-free assays were evident. Therefore, immobilized KBA (linked to Sepharose beads) selectively precipitated p12-LO from platelet lysates but failed to bind cPLA2. Taken together, we show that boswellic acids induce the release of arachidonic acid and the synthesis of 12-H(P)ETE in human platelets by unique Ca2+-independent routes, and we identified p12-LO as a selective molecular target of boswellic acids.

Footnotes

  • This study was supported by the Deutsche Forschungsgemeinschaft (WE 2260/4-1 and GRK 757).

  • ABBREVIATIONS: cPLA2, cytosolic phospholipase A2; Aβ-BA, 3-O-acetyl-boswellic acid; AKBA, 3-O-acetyl-11-keto-boswellic acid; CDC, cinnamyl-3,4-dihydroxy-α-cyanocinnamate; 12-H(P)ETE, 12-hydro(pero)xyeicosatetraenoic acid; KBA, 11-keto-boswellic acid; MAFP, methylarachidonyl-fluorophosphonate; MAPK, mitogen-activated protein kinase; p12-LO, platelet-type 12-lipoxygenase; PG buffer, phosphate-buffered saline and glucose; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PMNL, polymorphonuclear leukocytes; SDS-b, 2× SDS-polyacrylamide gel electrophoresis sample loading buffer; PAGE, polyacrylamide gel electrophoresis; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; AM, acetoxymethyl ester; Seph, Sepharose beads without ligand; Seph-KBA, Sepharose beads linked with 11-keto-boswellic acid; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SU6656, 2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylene)-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; A23187, calcimycin; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; PP3, 4-amino-7-phenylpyrazol[3,4-d]pyrimidine.

    • Received March 22, 2006.
    • Accepted June 20, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (3)
Molecular Pharmacology
Vol. 70, Issue 3
1 Sep 2006
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Research ArticleArticle

Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca2+ and Differentially Interact with Platelet-Type 12-Lipoxygenase

Daniel Poeckel, Lars Tausch, Nicole Kather, Johann Jauch and Oliver Werz
Molecular Pharmacology September 1, 2006, 70 (3) 1071-1078; DOI: https://doi.org/10.1124/mol.106.024836

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Research ArticleArticle

Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca2+ and Differentially Interact with Platelet-Type 12-Lipoxygenase

Daniel Poeckel, Lars Tausch, Nicole Kather, Johann Jauch and Oliver Werz
Molecular Pharmacology September 1, 2006, 70 (3) 1071-1078; DOI: https://doi.org/10.1124/mol.106.024836
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