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SAT0030 Release of Secondary Mediators of Inflammation by Human Secretory Phospholipases A2 (SPLA2's)
  1. W. Pruzanski1,1,
  2. A. Kuksis
  1. Medicine and Biochemistry, University of Toronto/Banting and Best Medical Research, Toronto, CANADA, Toronto, Canada

Abstract

Background Proinflammatory and proatheromatous activity of sPLA2's IIA, V and X have been well documented. High levels of sPLA2 IIA were found in various arthritides. All 3 were found in the vascular wall. sPLA2 IIA was recovered from synovial cells, chondrocytes and cartilage. sPLA2 IIA was also found to induce joint tissue inflammation. Yet, with the exception of the effect on HDL/LDL and on mitogenic activity and the release of PGE2 and LTB4 from vascular smooth muscle cells, little is known about the cascade of events and production of secondary pro-inflammatory mediators that these sPLA2's may induce.

Objectives Investigation of the cascade of events that occurs when sPLA2's hydrolyse HDL and LDL and release proinflammatory mediators. 2. Study of chemotactic activity of vascular smooth muscle cells exposed to sPLA2's.

Methods Cultures of VSMC, origins of recombinant human sPLA2's, IIA, V and X, source of HDL and LDL, study of lipoproteins and of products of oxidation such as hydroxides, hydroxyperoxides, isoprostanes and epoxides by LC/ESI - MS were reported (1,2). Migration of VSMC cells was tested by modified Boyden Chamber with Falcon 24-Well Insert System using PDGF-bb as a control. Statistical analysis was performed by Microsoft Excel, and data reported as the means ± SD.

Results It was found that sPLA2 IIA, V and X – hydrolysed HDL and LDL release to various extents free F2-isoprostanes, hydroxides, hydroxyperoxides and epoxides from lipoprotein phospholipids. sPLA2's, V and X were more active than IIA. In turn, Ptd Cho isoprostanes promoted hydrolysis of lipoprotein Ptd Cho by sPLA2 IIA. sPLA2's differed in their preference for hydrolysis of oligoenoic and polyenoic Ptd Cho from plasma lipoproteins, V preferring linoleoyl Gro-PCHO, X preferring arachidonyl Gro-PCHO and IIA having no preference. Migration of VSMC was markedly enhanced by sPLA2 IIA in the dose/time manner, whereas, sPLA2, V and X did not induce chemotaxis.

Conclusions The above findings show that hydrolytic activity of various sPLA2's is not identical, but in general it induces the release of a group of substances which per se are proinflammatory and that sPLA2 IIA but not V or X induces chemotactic activity of VSMC. These results show previously unrecognized complexity of activity of human sPLA2, IIA, V and X, all of which participate in rheumatological conditions. Hydrolysis of auto-oxidized lipoproteins by sPLA2's releases secondary mediators of inflammation which were not recognized before.

References

  1. Pruzanski W, et. al. Lab. Invest. 81:757, 2001. 2. Kuksis A and Pruzanski, 104 AOCS Ann. Meeting, 2013, Montreal, P.Q. Canada.

Disclosure of Interest None declared

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