Macrophage-specific overexpression of group IIa sPLA2 increases atherosclerosis and enhances collagen deposition.
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.
Ghesquiere
Stijn A I
SA
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Gijbels
Marion J J
MJ
Anthonsen
Marit
M
van Gorp
Patrick J J
PJ
van der Made
Ingeborg
I
Johansen
Berit
B
Hofker
Marten H
MH
de Winther
Menno P J
MP
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism*; D015152:Blotting, Northern; D016026:Bone Marrow Transplantation; D039481:CD11b Antigen / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D054501:Group II Phospholipases A2; D006801:Humans; D020287:In Situ Nick-End Labeling; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009336:Necrosis; D010641:Phenotype; D010740:Phospholipases / Q000737:chemistry; D010741:Phospholipases A / Q000096:biosynthesis*; D054467:Phospholipases A2; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D013997:Time Factors
D039481:CD11b Antigen; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D003094:Collagen; D002784:Cholesterol; D010740:Phospholipases; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2