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THU0551 Secretory Phospholipases as Mediators of Inflammatory and Proatheromatous Changes in Rheumatic Diseases
  1. W. Pruzanski1,
  2. A. Kuksis2
  1. 1Medicine, University of Toronto, Toronto, Canada
  2. 2Biochemistry, Banting and Best Medical Research, Toronto, Canada

Abstract

Background Inflammatory vascular changes and enhanced atheromatosis are well known in rheumatic diseases. Mitogenesis of vascular smooth muscle cells (VSMC) in above conditions is of prime importance. Secretory phospholipase A2 (sPLA2), which is known to induce mitogenesis, was found in and cloned from the synovial fluid (1,2). High serum levels of sPLA2 were found in various rheumatic diseases (3-6). sPLA2 was found in synovial cells (7) human cartilage (8) and chondrocytes (9). Pro-inflammatory effect of sPLA2 on joint tissue was reported (10).

Objectives To investigate the role of sPLA2 IIA, V and X on mitogenesis of VSMC, release of PGE2 and LTB4 and effect on lipoproteins. Furthermore, the effects of enzyme hydrolysis of pro-inflammatory products of Oxo-PtdCho were investigated.

Methods Cultures of VSMC, study of mitogenesis, origins of sPLA2's and lipoproteins were reported (11). The analyses of the products of PtdCho oxidation, such as core aldehydes, isoprostanes, hydroxides and hydroxyperoxides were done by LC/ESI-MS.PGE2 and LTB4 release were tested by EIA systems.

Results Exposure of VSMC to sPLA2 IIA or X did not increase mitogenesis, whereas exposure to grV markedly increased it in a dose/time fashion. Likewise, VSMC exposed to HDL or LDL hydrolysed by sPLA2 V (and less by X) became mitogenic. Interaction of sPLA2 with lipoproteins showed that hydrolysis of HDL and LDL by sPLA2's and the impact on mitogenesis were invariably enhanced in order V>X>IIA. Release of PGE2 was enhanced by sPLA2 X and LTB4 by gr X and V. Investigation of the products of lipoproteins hydrolysis showed that there is formation of core aldehydes, isoprostanes, hydroxides and hydroperoxides of PtdCho. sPLA2 grV hydrolysed hydroxides and hydroxyperoxides of linoleolyl GroPCho in preference to arachidonoyl GroPCho while groups IIA and X did the opposite.

Conclusions The above studies show diverse activity of sPLA2's gr IIA, V and X on mitogenesis of VSMC (early activation of inflammation) and on release of PGE2 and LTB4 from VSMC (late phase of proinflammatory activity). Further study showed differences between the effects of sPLA2 V as opposed to IIA and X on mitogenesis and on hydrolysis of lipoproteins, showing the complexity of mitogenic proinflammatory response. Further studies directed to block sPLA2's especially V in inflammation and enhanced atherogenesis in rheumatic diseases is advisable.

References

  1. Stefanski E. et. al. J. Biochem.100:1297, 1986.

  2. Seilhamer J.J. et al. J. Biol. Chem. 264:5335, 1981.

  3. Pruzanski W. et al. J. Rheumat. 15:1601, 1988.

  4. J. Rheumat. 18:117, 1991.

  5. J. Rheumat. 21:1951, 1994.

  6. J. Rheumat. 21:252, 1994.

  7. J. Rheumat. 15:791, 1988.

  8. J. Rheumat. 17:569, 1990.

  9. J. Rheumat. 17:1386, 1990.

  10. J. Rheumat. 13:1990, 1986.

  11. Lab. Invest. 81:757, 2001.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.1520

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