Novel caffeic acid derivatives: extremely potent inhibitors of 12-lipoxygenase

Cho, H; Ueda, Masaru; Tamaoka, Masami; Hamaguchi, M.; Aisaka, Kazuo; Kiso, Yoshinobu; Inoue, Teruyoshi; Ogino, Ryoko; Tatsuoka, Toshio; Ishihara, Takafumi

doi:10.1021/jm00108a039

Cited by 109 publications

(71 citation statements)

References 3 publications

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“…To test 12(S)-HETE dependence of MARCKS phosphorylation we pretreated GCPs with CDC, a selective inhibitor of LOs, including 12/15-LO (48). Although CDC alone did not alter control levels of phosphorylation (data not shown), the LO inhibitor attenuated thrombin-stimulated MARCKS phosphorylation significantly (p Ͻ 0.015; Figs.…”

Section: Resultsmentioning

confidence: 93%

Eicosanoid Activation of Protein Kinase C ϵ

Mikule

Sunpaweravong

Gatlin

et al. 2003

Journal of Biological Chemistry

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Exposure of growing neurons to thrombin or semaphorin 3A stimulates a receptor-mediated signaling cascade that results in collapse of their growth cones. This collapse response necessitates eicosanoid production, as we have shown earlier. The present report investigates whether and which protein kinase C (PKC) isoforms may be activated by such eicosanoids. To examine these questions, we isolated growth cones from fetal rat brain and tested whether thrombin or the eicosanoid, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), could activate endogenous growth cone PKC. We show that both thrombin and 12(S)-HETE stimulate the phosphorylation of the myristoylated alanine-rich protein kinase C substrate, an 87-kDa adhesion site protein. Furthermore, we show both with immunoprecipitated and with recombinant PKC that 12(S)-HETE activation is selective for the ⑀ isoform and does not require accessory proteins. Last, we demonstrate that PKC activation is necessary for thrombin-induced growth cone collapse. These data indicate that eicosanoid-mediated repellent effects result from the direct and selective activation of PKC⑀ and suggest the involvement of myristoylated alanine-rich protein kinase C substrate phosphorylation in growth cone collapse.

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Section: Resultsmentioning

confidence: 93%

Eicosanoid Activation of Protein Kinase C ϵ

Mikule

Sunpaweravong

Gatlin

et al. 2003

Journal of Biological Chemistry

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“…Catechols and compounds containing phenolic groups have been reported to inhibit pl12-LO activity [38][39][40][41]. Given the structure of the vanilloids and their minimal oxygenation by pl12-LO, the ability of these compounds to inhibit pl12-LO was determined.…”

Section: Lo Inhibition By Nadamentioning

confidence: 99%

Oxidative metabolism of lipoamino acids and vanilloids by lipoxygenases and cyclooxygenases

Prusakiewicz¹,

Turman²,

Vila³

et al. 2007

Archives of Biochemistry and Biophysics

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The lipoamino acids and endovanilloids have multiple roles in nociception, pain, and inflammation, yet their biological reactivity has not been fully characterized. Cyclooxygenases (COXs) and lipoxygenases (LOs) oxygenate polyunsaturated fatty acids to generate signaling molecules. The ability of COXs and LOs to oxygenate arachidonyl-derived lipoamino acids and vanilloids was investigated. COX-1 and COX-2 were able to minimally metabolize many of these species. However, the lipoamino acids were efficiently oxygenated by 12S-and 15S-LOs. The kinetics and products of oxygenation by LOs were characterized. Whereas 15S-LOs retained positional specificity of oxygenation with these novel substrates, platelet-type 12S-LO acted as a 12/15-LO. Fatty acid oxygenases may play an important role in the metabolic inactivation of lipoaminoacids or vanilloids or may convert them to bioactive derivatives.

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“…CDC blocks platelet 12-LO and 12/15-LO expression in EC (36). The DNA/RNA hammerhead ribozyme was generated to recognize the first 7 bp of the porcine and murine 12/15-LO mRNA sequences (30).…”

Section: /15-lo Products Directly Stimulate Monocyte/endothelialmentioning

confidence: 99%

12/15-Lipoxygenase Activity Mediates Inflammatory Monocyte/Endothelial Interactions and Atherosclerosis in Vivo

Reilly

Srinivasan

Hatley

et al. 2004

Journal of Biological Chemistry

139

109

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We have shown that the 12/15-lipoxygenase (12/15-LO) product 12S-hydroxyeicosatetraenoic acid increases monocyte adhesion to human endothelial cells (EC) in vitro. Recent studies have implicated 12/15-LO in mediating atherosclerosis in mice. We generated transgenic mice on a C57BL/6J (B6) background that modestly overexpressed the murine 12/15-LO gene (designated LOTG). LOTG mice had 2.5-fold elevations in levels of 12S-hydroxyeicosatetraenoic acid and a 2-fold increase in expression of 12/15-LO protein in vivo. These mice developed spontaneous aortic fatty streak lesions on a chow diet. Thus, we examined effects of 12/15-LO expression on early events leading to atherosclerosis in these mice. We found that, under basal unstimulated conditions, LOTG EC bound more monocytes than B6 control EC (18 ؎ 2 versus 7 ؎ 1 monocytes/field, respectively; p < 0.0001). Inhibition of 12/15-LO activity in LOTG EC using a 12/15-LO ribozyme completely blocked monocyte adhesion in LOTG mice. Thus, 12/15-LO activity is required for monocyte/EC adhesion in the vessel wall. Expression of ICAM-1 in aortic endothelia of LOTG mice was increased severalfold. VCAM-1 expression was not changed. In a series of blocking studies, antibodies to ␣ 4 and ␤ 2 integrins in WEHI monocytes blocked monocyte adhesion to both LOTG and B6 control EC. Inhibition of ICAM-1, VCAM-1, and connecting segment-1 fibronectin in EC significantly reduced adhesion of WEHI monocytes to LOTG EC. In summary, these data indicate that EC from LOTG mice are "pre-activated" to bind monocytes. Monocyte adhesion in LOTG mice is mediated through ␤ 2 integrin and ICAM-1 interactions as well as through VLA-4 and connecting segment-1 fibronectin/ VCAM-1 interactions. Thus, 12/15-LO mediates monocyte/EC interactions in the vessel wall in atherogenesis at least in part through molecular regulation of expression of endothelial adhesion molecules.Murine 12/15-lipoxygenase (12/15-LO) 1 incorporates molecular oxygen in a stereospecific manner into arachidonic and linoleic acids to generate 12S-and 15S-hydroxyeicosatetraenoic acids (12S-HETE) and 13S-hydroxyoctadecadienoic acid (13S-HODE) (1-3). Murine 12/15-LO is similar biochemically and structurally to the porcine leukocyte-type 12-LO and human 15-LO enzymes (2-4). There also exists a murine platelet 12-LO, which utilizes arachidonic acid solely as a substrate to generate 12S-HETE (4, 5).The exact biologic functions of 12/15-LO are unknown. However, considerable evidence exists to support a role for 12/ 15-LO in promoting both diabetes and atherosclerosis (6 -9). Nadler and co-workers (6) have shown that mice deficient in 12/15-LO are protected from development of low dose streptozotocin-induced diabetes. We have recently shown that diabetic db/db mice produce significant quantities of 12S-HETE in vivo (10). Importantly, using a catalytic ribozyme to inactivate 12/ 15-LO mRNA, we have shown that disruption of 12/15-LO mRNA in diabetic db/db mice blocks monocyte adhesion (10). Striking evidence for the role of 12/15-LO in atherogenes...

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Novel caffeic acid derivatives: extremely potent inhibitors of 12-lipoxygenase

Cited by 109 publications

References 3 publications

Eicosanoid Activation of Protein Kinase C ϵ

Eicosanoid Activation of Protein Kinase C ϵ

Oxidative metabolism of lipoamino acids and vanilloids by lipoxygenases and cyclooxygenases

12/15-Lipoxygenase Activity Mediates Inflammatory Monocyte/Endothelial Interactions and Atherosclerosis in Vivo

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