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,Menno P.J De Winther

doi:10.1194/jlr.m400253-jlr200

Stijn A.I Ghesquiere, Marion J.J Gijbels + Show 6 more

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https://doi.org/10.1194/jlr.m400253-jlr200

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Abstract

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.

Highlights

Atherosclerosis is a chronic inflammatory disease of the vessel wall characterized by the accumulation of lipidladen macrophages and fibrotic material
Group IIa secretory phospholipase A2 has been detected in atherosclerotic lesions in CD68-positive macrophages [5,6,7]. sPLA2 IIa can hydrolyze LDL-associated phospholipids, resulting in the formation of the so-called “bioactive” lipids, such as lysophospholipids and arachidonic acid. sPLA2 IIa is a member of a large family of related enzymes that are able to catalyze the hydrolysis of phospholipids at the sn-2 ester bond, a process that results in the generation of free fatty acids and lysophospholipids [8]. sPLA2 IIa is widely expressed in the human body [9] and is considered to be important in the amplification of inflammation in many disease processes, including atherosclerosis [6, 7, 10, 11]
We examined the effects of macrophage sPLA2 IIa on atherogenesis

Summary

Introduction

Atherosclerosis is a chronic inflammatory disease of the vessel wall characterized by the accumulation of lipidladen macrophages and fibrotic material. 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. 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 fibrotic cap development.—Ghesquiere, S. Macrophage-specific overexpression of group IIa sPLA2 increases atherosclerosis and enhances collagen deposition. Grass et al [19] generated a transgenic mouse model to study the role of sPLA2 IIa in inflammation In this model, the human sPLA2 IIa gene was used with its own promoter

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