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Journal of Lipid Research, Vol. 46, 201-210, February 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Macrophage-specific overexpression of group IIa sPLA₂ increases atherosclerosis and enhances collagen deposition

Stijn A. I. Ghesquiere^*, Marion J. J. Gijbels^*,, Marit Anthonsen, Patrick J. J. van Gorp^*, Ingeborg van der Made^*, Berit Johansen, Marten H. Hofker^* and Menno P. J. de Winther^1,*

^* Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Department of Biology, Section on Molecular Biology and Biotechnology, Norwegian University of Science and Technology, Trondheim, Norway

¹ To whom correspondence should be addressed. e-mail: dewinther{at}gen.unimaas.nl

Atherosclerosis is a chronic inflammatory disease of the vessel wall characterized by the accumulation of lipid-laden macrophages and fibrotic material. The initiation of the disease is accompanied by the accumulation of modified lipoproteins in the vessel wall. Group IIa secretory phospholipase A₂ (sPLA₂ IIa) is a key candidate player in the enzymatic modification of low density lipoproteins. To study the role of sPLA₂ IIa in macrophages during atherogenesis, transgenic mice were generated using the human sPLA₂ IIa gene and the CD11b promoter. Bone marrow transplantation to LDL receptor-deficient mice was performed to study sPLA₂ IIa in atherosclerosis. After 10 weeks of high-fat diet, mice overexpressing sPLA₂ IIa in macrophages showed 2.3-fold larger lesions compared with control mice. Pathological examination revealed that sPLA₂ IIa-expressing mice had increased collagen in their lesions, independent of lesion size. However, smooth muscle cells or fibroblasts in the lesions were not affected. Other parameters studied, including T-cells and cell turnover, were not significantly affected by overexpression of sPLA₂ IIa in macrophages.

These data clearly show that macrophage sPLA₂ IIa is a proatherogenic factor and suggest that the enzyme regulates collagen production in the plaque and thus fibrotic cap development.

Supplementary key words atherogenesis • lipid modification • inflammation • secretory phospholipase A₂

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