The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A2 and suppress PGE2 formation in mesangial cells

• DOI: 10.1111/j.1476-5381.2012.02114.x
• Publication Date: 2012-07-25T13:03:40Z
• Authors: Andrea Huwiler; Astrid J Feuerherm; Benjamin Sakem; Oleksandr Pastukhov; Iuliia Filipenko; Thuy Nguyen; Berit Johansen
• Keywords: 0301 basic medicine; Phospholipase A2 Inhibitors; Anti-Inflammatory Agents; NF-kappa B; Dinoprostone; Rats; 03 medical and health sciences; Cytosol; Fatty Acids, Omega-3; Mesangial Cells; Animals; Enzyme Inhibitors; Cells, Cultured

Background and Purposeω3‐polyunsaturated fatty acids (ω3‐PUFAs) are known to exert anti‐inflammatory effects in various disease models although their direct targets are only poorly characterized.Experimental approachHere we report on two new cPLA2 inhibitors, the ω3‐derivatives AVX001 and AVX002, and their effects on inflammatory PGE2 production in cultures of renal mesangial cells.Key ResultsAVX001 and AVX002 dose‐dependently inhibited the group IVA cytosolic phospholipase A2 (cPLA2) in an in vitro activity assay with similar IC50 values for AVX001 and AVX002, whereas the known cPLA2 inhibitor AACOCF3 was less potent and docosahexaenoic acid (DHA) was inactive. In renal mesangial cells, AVX001 and AVX002 suppressed IL‐1β‐induced PGE2 synthesis. Mechanistically, this effect occurred by a down‐regulation of IL‐1β‐induced group IIA‐sPLA2 protein expression, mRNA expression and promoter activity. A similar but less potent effect was seen with AACOCF3 and no effect was seen with DHA. As gene expression of sPLA2 is known to be regulated by the transcription factor NF‐κB, we further investigated NF‐κB activation. Both compounds prevented NF‐κB activation by blocking degradation of the inhibitor of κB.Conclusions and implicationsThese data show for the first time that the novel cPLA2 inhibitors AVX001 and AVX002 exert an anti‐inflammatory effect in cultures of renal mesangial cells and reduce the pro‐inflammatory mediator PGE2 through an inhibitory effect on NF‐κB activation. Therefore, these compounds may represent promising novel drugs for the treatment of inflammatory disorders.