Group IVA phospholipase A2-associated production of MMP-9 in macrophages and formation of atherosclerotic lesions.
Matrix metalloproteinase-9 (MMP-9) is involved in atherogenesis, and the production of MMP-9 in macrophages is considered to be mediated by the arachidonic acid cascade. The present study examined the possible involvement of group IVA phospholipase A2 (IVA-PLA2), a key enzyme in the arachidonic acid cascade, in the production of MMP-9 induced by oxidized low-density lipoprotein (oxLDL) in macrophages and high-fat diet-induced formation of atherosclerotic lesions using IVA-PLA2-deficient mice (C57BL/6 background). In wild-type mouse peritoneal macrophages, oxLDL induced an increase in MMP-9 in the culture medium. The oxLDL-promoted production of MMP-9 was markedly reduced in IVA-PLA2-deficient macrophages compared to wild-type macrophages. Feeding of wild-type mice with a high-fat diet caused the formation of early atherosclerotic lesions in the aortic root with increases in MMP-9 and macrophages in the lesions and with higher serum levels of total cholesterol. Such lesions were apparently less severe in IVA-PLA2-deficient mice fed a high-fat diet, despite higher total cholesterol levels. Under the conditions, a high-fat diet reduced the serum levels of high-density lipoprotein-cholesterol (HDL-C) in wild-type mice. However, IVA-PLA2-deficient mice fed a high-fat diet were protected against the decrease in HDL-C levels. The present results suggest that IVA-PLA2 is involved in the oxLDL-induced production of MMP-9 in macrophages and the high-fat diet-induced formation of early atherosclerotic lesions. The protection against the lesions in IVA-PLA2-deficient mice may be ascribable, in part, to the impaired production of MMP-9 and/or the maintained levels of HDL-C.
Ii
Hiromi
H
Department of Pathological Biochemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Hontani
Naoya
N
Toshida
Issei
I
Oka
Mayuko
M
Sato
Takashi
T
Akiba
Satoshi
S
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D016718:Arachidonic Acid / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D054513:Group IV Phospholipases A2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D004041:Dietary Fats; D008055:Lipids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2; D020780:Matrix Metalloproteinase 9