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Acta Physiologica Congress

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Acta Physiologica 2012; Volume 204, Supplement 689
91st Annual Meeting of The German Physiological Society
3/22/2012-3/25/2012
Dresden, Germany


SHEAR STRESS-INDUCED 15-DEOXY-12,14-PROSTAGLANDIN J2 FORMATION REINFORCES THE ANTI-INFLAMMATORY CAPACITY OF ENDOTHELIAL CELLS WITH A GENETIC DEFECT IN NITRIC OXIDE SYNTHESIS
Abstract number: O32

Yakubenia1 *S., Cattaruzza1 M., Hecker1 M.

1University of Heidelberg, Institute of Physiology and Pathophysiology, Heidelberg, Germany

Question:

Individuals homozygous for the T-786C SNP of the endothelial nitric oxide (NO) synthase gene have an increased risk to contract coronary heart disease due to the relative insensitivity of the C-variant to fluid shear stress (FSS) resulting in a reduced NO synthesis capacity. However, there are at least two mechanisms by which this genetically determined dysfunction can be overcome, one of which was investigated herein.

Methods:

Human umbilical vein endothelial cells (EC) were genotyped for the T-786C SNP, and CC genotype cells were compared to TT genotype ECs throughout. Expression of arachidonic acid-metabolizing enzymes was investigated by both quantitative PCR and Western blot analysis. 15-Deoxy-D12,14-prostaglandin J2 (15d-PGJ2) released was determined by EIA. Human monocytic THP-1 cells were employed to interact with the CC or TT genotype ECs.

Results:

Exposing the ECs to FSS effectively reduced THP-1 cell migration not only through TT but also through the NO-deficient CC genotype cells, pointing to the existence of a compensatory mechanism. Both cyclooxygenase-2 and lipocalin-type prostaglandin D synthase (L-PGDS) expression was up-regulated by FSS solely in CC genotype ECs, and siRNA-mediated down-regulation of L-PGDS significantly enhanced THP-1 cell migration through the CC genotype EC monolayer. Moreover, only these cells released 15d-PGJ2, the ultimate metabolite of the L-PGDS pathway, in response to FSS, and 15d-PGJ2 effectively abrogated pro-inflammatory activation of the THP-1 cells.

Conclusions:

Despite a reduced capacity to form NO, CC genotype ECs reveal a robust anti-inflammatory phenotype due to an up-regulation of 15d-PGJ2 synthesis in response to FSS. Its inhibitory effect on e.g. interleukin-1b expression in monocytes is not mediated by one of the classical fatty acid signalling mechanisms but involves the activation of an as yet unidentified inhibitory transcription factor.

To cite this abstract, please use the following information:
Acta Physiologica 2012; Volume 204, Supplement 689 :O32

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