FLAP (5-lipoxygenase-activating protein) is a nuclear transmembrane protein involved in the biosynthesis of LTs (leukotrienes) and other 5-LO (5-lipoxygenase) products. However, little is known about its mechanism of action. In the present study, using cross-linkers, we demonstrate that FLAP is present as a monomer and a homodimer in human PMN (polymorphonuclear cells). The functional relevance of the FLAP dimer in LT biosynthesis was assessed in different experimental settings. First, the 5-LO substrate AA (arachidonic acid) concomitantly disrupted the FLAP dimer (at ≥10 μM) and inhibited LT biosynthesis. Secondly, using Sf9 cells expressing active and inactive FLAP mutants and 5-LO, we observed that the FLAP mutants capable of supporting 5-LO product biosynthesis also form the FLAP dimer, whereas inactive FLAP mutants do not. Finally, we showed that FLAP inhibitors such as MK-0591 which block LT biosynthesis in human PMN, disrupt the FLAP dimer in PMN membranes with a similar IC50. The present study demonstrates that LT biosynthesis in intact cells not only requires the presence of FLAP but its further organization into a FLAP homodimer.

14 Jul 1998·CirculationQ1 · MEDICINE

Induction of Cyclooxygenase-2 and Activation of Nuclear Factor-κB in Myocardium of Patients With Congestive Heart Failure

Q1 · MEDICINE

Article

Author: Rodger, Ian ; Giaid, Adel ; Melnyk, Peter ; Wong, Samuel C. Y. ; Fukuchi, Mitsumasa

Background —Chronic heart failure is associated with induction of secondary inflammatory mediators, including prostanoids. The latter exert diverse functional and morphological effects on cardiac myocytes. Induction of cyclooxygenase (COX), the enzyme responsible for generating prostanoids, requires activation of nuclear factor-κB (NF-κB). The aim of the present study was to determine the expression of COX-2 and activation of NF-κB in the failing human heart. Methods and Results —Myocardial tissue from 27 patients with end-stage heart failure (various etiologies: ischemic heart disease, n=16; idiopathic dilated cardiomyopathy, n=10; and valvular heart disease, n=1), 2 septic patients, and 8 normal control subjects was immunostained with antisera to COX-2 and NF-κB. Western blotting was performed and showed high anti–COX-2 antibody specificity and the presence of COX-2 protein in the sample tissues. In situ hybridization and immunohistochemistry showed little or no expression of COX-2 and NF-κB in the control hearts. In contrast, there was abundant expression of COX-2 mRNA and protein in myocytes and inflammatory cells in areas of fibrotic scar compared with regions of normal morphology in all cases of heart failure, except the cases with sepsis, which showed an abundance of COX-2 throughout the myocardium. Sites of NF-κB activation were associated with those of COX-2 expression. Conclusions —We demonstrate induction of COX-2 and activation of NF-κB in the myocardium of failing human hearts. Induction of both molecules appears to be associated with the presence of inflammation and scar formation.

01 Oct 1982·The Journal of Organic Chemistry

Synthesis and stereochemistry of 11-substituted 5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctenes

Author: Scheigetz, John S. ; Dufresne, Claude ; Belanger, Patrice C. ; Young, Robert N. ; Springer, James P.

5,6,7,8,9,10-Hexahydro-6,9-methanobenzocyclooctene (I) is a ring system where the cyclooctene ring could be in a boat or in a chair conformation.Mol. modeling calculations indicated that the boat conformation is favored when C-11 is substituted by a ketone group, an amino group, or a hydroxy group; this is confirmed by NMR shift reagent studies.Chem. modifications of C-11 from a sp² to sp³ C (i.e., reduction of carbonyl to alc.) gives only endo derivativesAttempts to obtain the exo derivatives by displacement reactions of sulfonates or Ritter reactions failed.The only exo derivative obtainable was 11-exo-amino-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene, isolated in low yields from the base-catalyzed equilibration of its N-benzylidene derivative

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