Secretory Phospholipase A2 and Lipoprotein Lipase Enhance 15-Lipoxygenase-Induced Enzymic and Nonenzymic Lipid Peroxidation in Low-Density Lipoproteins
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- 作者：Jirí ; Neuzil ; Joanne M. Upston ; Paul K. Witting ; Kieran F. Scott ; and Roland Stocker
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：June 23, 1998
- 年：1998
- 卷：37
- 期：25
- 页码：9203 - 9210
- 全文大小：100K
- 年卷期：v.37,no.25(June 23, 1998)
- ISSN：1520-4995
文摘
The oxidation of low-density lipoprotein (LDL) isthought to contribute to atherogenesis. 15-Lipoxygenase (15LO) induces LDL oxidation, and phospholipaseA2 enhances this process [Sparrow, C.P., Parthasarathy, S., and Steinberg, D. (1988) J. LipidRes. 29, 745-753]. As the underlyingmechanismof the enhancing effect has not been investigated previously, we hereshow that in the presence of soybean15LO (SLO) or human 15LO (rhLO), the addition of lipoprotein lipase,porcine pancreatic, or humantype IIa secretory phospholipase A2 (sPLA2)greatly enhanced the accumulation of hydro(pero)xidesofall major classes of LDL's lipids. Hydroperoxides of free fattyacids accumulated exclusively as enzymicproducts with kinetics reflecting both the formation of free fattyacids and the initial 'build-up' of
-tocopheroxyl radical. In contrast, hydroperoxides ofcholesteryl esters and phosphatidylcholineaccumulated linearly over comparatively longer periods of time and, inthe case of rhLO, well beyondinactivation of the oxygenase. With SLO, formation of oxidizedesterified lipids occurred nonenzymically,independent of the presence of lipase and despite the oxygenaseremaining active until the end of theincubation. Enhancement of rhLO-induced LDL lipid peroxidation bysPLA2 was eliminated by aneutralizing anti-sPLA2 antibody, indicating that lipolyticactivity was required for this effect. LDL depletedof -tocopherol was resistant to oxidation by 15LO alone, whereaslipase overcame this resistance,demonstrating that lipases enhance 15LO-induced enzymic and nonenzymicperoxidation of LDL lipids.This is likely due to provision of free fatty acid substrate,resulting in an enhanced rate of free radicalformation which itself causes nonenzymic peroxidation of esterifiedlipids. As lipases and 15LO arepresent in atherosclerotic lesions, our findings could be ofpathophysiological significance.
-tocopheroxyl radical. In contrast, hydroperoxides ofcholesteryl esters and phosphatidylcholineaccumulated linearly over comparatively longer periods of time and, inthe case of rhLO, well beyondinactivation of the oxygenase. With SLO, formation of oxidizedesterified lipids occurred nonenzymically,independent of the presence of lipase and despite the oxygenaseremaining active until the end of theincubation. Enhancement of rhLO-induced LDL lipid peroxidation bysPLA2 was eliminated by aneutralizing anti-sPLA2 antibody, indicating that lipolyticactivity was required for this effect. LDL depletedof -tocopherol was resistant to oxidation by 15LO alone, whereaslipase overcame this resistance,demonstrating that lipases enhance 15LO-induced enzymic and nonenzymicperoxidation of LDL lipids.This is likely due to provision of free fatty acid substrate,resulting in an enhanced rate of free radicalformation which itself causes nonenzymic peroxidation of esterifiedlipids. As lipases and 15LO arepresent in atherosclerotic lesions, our findings could be ofpathophysiological significance.