Group V and X secretory phospholipase A(2)s-induced modification of high-density lipoprotein linked to the reduction of its antiatherogenic functions.
The quantitative or qualitative decline of high-density lipoprotein (HDL) is linked to the pathogenesis of atherosclerosis because of its antiatherogenic functions, including the mediation of reverse cholesterol transport from the peripheral cells to the liver. We have recently shown that group X secretory phospholipase A(2) (sPLA(2)-X) is involved in the pathogenesis of atherosclerosis via potent lipolysis of low-density lipoprotein (LDL) leading to macrophage foam cell formation. We demonstrate here that sPLA(2)-X as well as group V secretory PLA(2) (sPLA(2)-V), another group of sPLA(2) that can potently hydrolyze phosphatidylcholine (PC), also possess potent hydrolytic potency for PC in HDL linked to the production of a large amount of unsaturated fatty acids and lysophosphatidylcholine (lysoPC). In contrast, the classical types of group IB and IIA secretory PLA(2)s evoked little, if any, lypolytic modification of HDL. Treatment with sPLA(2)-X or -V also caused an increase in the negative charge of HDL with no oxidation and little modification of apolipoprotein AI (apoAI). Modification with sPLA(2)-X or -V resulted in significant decrease in the capacity of HDL to cause cellular cholesterol efflux from lipid-loaded macrophages. Immunohistochemical analysis revealed significant expression of sPLA(2)-X in foam cell lesions in the arterial intima of Watanabe heritable hyperlipidemic (WHHL) rabbit. These findings suggest that lipolytic modification of HDL by sPLA(2)-X or -V causes drastic change of HDL in terms of the production of a large amount of unsaturated fatty acids and lysoPC linked to the reduction of its antiatherogenic functions. These sPLA(2)-mediated modifications of plasma lipoproteins might be relevant to the pathogenesis of atherosclerosis.
Shionogi Research Laboratories, Shionogi and Co, Ltd, Sagisu 5-12-4, Fukushima, Osaka 553-0002, Japan.
Yoshikazu
Y
Ishimoto
Katsutoshi
K
Yamada
Shigenori
S
Yamamoto
Takashi
T
Ono
Mitsuru
M
Notoya
Kohji
K
Hanasaki
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000201:enzymology* / Q000473:pathology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D054505:Group V Phospholipases A2; D054509:Group X Phospholipases A2; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D010713:Phosphatidylcholines / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors
D005231:Fatty Acids, Unsaturated; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D010741:Phospholipases A; D054505:Group V Phospholipases A2; D054509:Group X Phospholipases A2; C516365:PLA2G10 protein, human; C516299:PLA2G5 protein, human; C516366:Pla2g10 protein, mouse; C516300:Pla2g5 protein, mouse