Oxidative Stress Is Markedly Elevated in Lecithin:Cholesterol Acyltransferase-deficient Mice and Is Paradoxically Reversed in the Apolipoprotein E Knockout Background in Association with a Reduction in Atherosclerosis

Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare cause of severe hypoalphalipoproteinemia, but the affected subjects are surprisingly not particularly prone to premature coronary heart disease. We studied oxidative stress in lcat−/− mice and their cross-breed with apolipoprotein-E knockout mice (apoE−/−xlcat−/−) by measuring vascular ring superoxide production and plasma phospholipid (PL)-bound F2-isoprostane levels and their relationship with aortic atherosclerosis. Compared with wild type control (lcat+/+), lcat−/− and lcat+/− mice showed a 4.9- (p = 0.003) and a 2.1-fold (p = 0.04) increase in plasma PL-F2-isoprostane levels, respectively. There was also a 3.6- (p < 0.0001) and 2.9-fold (p = 0.003) increase in the area under the curve for the aortic ring superoxide excursion by lucigenin-derived chemiluminescence. A comparison of apoE−/−xlcat+/+ mice with wild type control mice showed a more modest 2.1- (p = 0.04) and 2.2-fold (p < 0.00001) increase in these respective markers. Surprisingly, the apoE−/−xlcat−/− mice showed a paradoxical normalization in both oxidation markers. Furthermore, by fast protein liquid chromatography separation, we observed an associated retention and redistribution of serum paraoxonase activities to the non-high density lipoprotein fractions in both the apoE−/−xlcat−/− and apoE−/−xlcat+/− mice. Aortic atherosclerotic lesions in male apoE−/−xlcat−/− and apoE−/−xlcat+/− mice were reduced by 52 (p = 0.02) and 24% (p = 0.46), respectively. Our data suggest that LCAT-deficient mice are associated with an increased oxidative stress that is paradoxically reversed in a hyperlipidemic background, possibly due to the redistribution of paraoxonase. This modulation of oxidative stress may in part contribute to the reduced atherosclerosis seen in the apoE−/− xlcat−/− mice. Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare cause of severe hypoalphalipoproteinemia, but the affected subjects are surprisingly not particularly prone to premature coronary heart disease. We studied oxidative stress in lcat−/− mice and their cross-breed with apolipoprotein-E knockout mice (apoE−/−xlcat−/−) by measuring vascular ring superoxide production and plasma phospholipid (PL)-bound F2-isoprostane levels and their relationship with aortic atherosclerosis. Compared with wild type control (lcat+/+), lcat−/− and lcat+/− mice showed a 4.9- (p = 0.003) and a 2.1-fold (p = 0.04) increase in plasma PL-F2-isoprostane levels, respectively. There was also a 3.6- (p < 0.0001) and 2.9-fold (p = 0.003) increase in the area under the curve for the aortic ring superoxide excursion by lucigenin-derived chemiluminescence. A comparison of apoE−/−xlcat+/+ mice with wild type control mice showed a more modest 2.1- (p = 0.04) and 2.2-fold (p < 0.00001) increase in these respective markers. Surprisingly, the apoE−/−xlcat−/− mice showed a paradoxical normalization in both oxidation markers. Furthermore, by fast protein liquid chromatography separation, we observed an associated retention and redistribution of serum paraoxonase activities to the non-high density lipoprotein fractions in both the apoE−/−xlcat−/− and apoE−/−xlcat+/− mice. Aortic atherosclerotic lesions in male apoE−/−xlcat−/− and apoE−/−xlcat+/− mice were reduced by 52 (p = 0.02) and 24% (p = 0.46), respectively. Our data suggest that LCAT-deficient mice are associated with an increased oxidative stress that is paradoxically reversed in a hyperlipidemic background, possibly due to the redistribution of paraoxonase. This modulation of oxidative stress may in part contribute to the reduced atherosclerosis seen in the apoE−/− xlcat−/− mice. Lecithin:cholesterol acyltransferase (LCAT) 1The abbreviations used are: LCATlecithin:cholesterol acyltransferaseapoEapolipoprotein EkoknockoutLDCL-AUClucigenin-derived chemiluminescence-area under the curvePL-F2-isoPphospholipid (glycerol-phosphocholine)-bound F2-isoprostanePONparaoxonaseLDLlow density lipoproteinIDLintermediate density lipoproteinHDLhigh density lipoproteinPLphospholipidNOnitric oxideFCfree cholesterolCEcholesterol esterFPLCfast protein liquid chromatographyANOVAanalysis of variancePAF-AHplatelet-activating factor acetylhydrolaseVLDLvery low density lipoproteinLpXlipoprotein X plays a central role in the reverse cholesterol transport process by mediating the esterification of tissue-derived free cholesterol (FC) and is responsible for the majority of esterified cholesterol (CE) in the circulation (1.Fielding C.J. Fielding P.E. J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar). Subjects with LCAT deficiency as a result of mutations of the LCAT gene invariably develop severe HDL deficiency, but surprisingly, these subjects do not seem to be particularly prone to premature coronary heart disease (2.Kuivenhoven J.A. Pritchard H. Hill J. Frohlich J. Assmann G. Kastelein J. J. Lipid Res. 1997; 38: 191-205Abstract Full Text PDF PubMed Google Scholar). The role of LCAT in atherosclerosis remains controversial. lecithin:cholesterol acyltransferase apolipoprotein E knockout lucigenin-derived chemiluminescence-area under the curve phospholipid (glycerol-phosphocholine)-bound F2-isoprostane paraoxonase low density lipoprotein intermediate density lipoprotein high density lipoprotein phospholipid nitric oxide free cholesterol cholesterol ester fast protein liquid chromatography analysis of variance platelet-activating factor acetylhydrolase very low density lipoprotein lipoprotein X Several lines of experimental evidence suggest that HDL may partially confer its anti-atherogenic action as an antioxidant through activities of its associated enzyme, paraoxonase (PON1) (3.Navab M. Hama S.Y. Anantharamaiah G.M. Hassan K. Hough G.P. Watson A.D. Reddy S.T. Sevanian A. Fonarow G.C. Fogelman A.M. J. Lipid Res. 2000; 41: 1495-1508Abstract Full Text Full Text PDF PubMed Google Scholar). Recent studies on PON1 ko mice (4.Shih D.M. Gu L. Xia Y.R. Navab M. Li W.F. Hama S. Castellani L.W. Furlong C.E. Costa L.G. Fogelman A.M. Lusis A.J. Nature. 1998; 394: 284-287Crossref PubMed Scopus (966) Google Scholar, 5.Shih D.M. Xia Y.R. Wang X.P. Miller E. Castellani L.W. Subbanagounder G. Cheroutre H. Faull K.F. Berliner J.A. Witztum J.L. Lusis A.J. J. Biol. Chem. 2000; 275: 17527-17535Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar) suggest that PON1 plays a major role as antioxidant in the prevention of atherosclerosis. The PON1 ko mice were found to develop accelerated atherosclerosis with and without the apoE deficiency background. We reported recently (6.Forte T.M. Oda M.N. Knoff L. Frei B. Suh J. Harmony J.A. Stuart W.D. Rubin E.M. Ng D.S. J. Lipid Res. 1999; 40: 1276-1283Abstract Full Text Full Text PDF PubMed Google Scholar) that LCAT-deficient mice have significantly lower levels of plasma PON1 arylesterase activities. A number of in vitro studies have also suggested that the LCAT enzyme itself may have intrinsic anti-oxidant properties (7.Subramanian V.S. Goyal J. Miwa M. Sugatami J. Akiyama M. Liu M. Subbaiah P.V. Biochim. Biophys. Acta. 1999; 1439: 95-109Crossref PubMed Scopus (56) Google Scholar, 8.Vohl M.C. Neville T.A. Kumarathasan R. Braschi S. Sparks D.L. Biochemistry. 1999; 38: 5976-5981Crossref PubMed Scopus (80) Google Scholar). It is therefore of considerable interest to understand better the in vivo effect of LCAT deficiency on oxidative stress and atherosclerosis in this mouse model. Vascular oxidant stress due to superoxide anion (O2⨪) and other reactive oxygen species has been implicated in the development of atherosclerosis (9.Griendling K.K. Sorescu D. Ushio-Fukai M. Circ. Res. 2000; 86: 494-501Crossref PubMed Scopus (2625) Google Scholar, 10.Yokoyama M. Inoue N. Kawashima S. Ann. N. Y. Acad. Sci. 2000; 902: 241-248Crossref PubMed Scopus (62) Google Scholar), possibly through being a major source of free radicals in the oxidative modification of low density lipoproteins (LDL) in the arterial wall (11.Gorlach A. Brandes R.P. Nguyen K. Amidi M. Dehghani F. Busse R. Circ. Res. 2000; 87: 26-32Crossref PubMed Scopus (542) Google Scholar). Excessive production of vascular O2⨪ also attenuates the bioavailability of endothelial derived nitric oxide (NO), which may contribute to endothelial dysfunction and atherosclerosis (12.O'Donnell V.B. Freeman B.A. Circ. Res. 2001; 88: 12-21Crossref PubMed Scopus (232) Google Scholar). Increasing evidence, both in vivo and in vitro, suggests that NAD(P)H oxidase is a major contributor to the generation of O2⨪ anions in the vascular wall (9.Griendling K.K. Sorescu D. Ushio-Fukai M. Circ. Res. 2000; 86: 494-501Crossref PubMed Scopus (2625) Google Scholar, 13.Guzik T.J. West N.E. Black E. McDonald D. Ratnatunga C. Pillai R. Channon K.M. Circ. Res. 2000; 86: E85-E90Crossref PubMed Google Scholar). In addition to oxidized lipids, the NAD(P)H oxidase activity has also been shown to be modulated by a number of vasoactive peptides, cytokines, and growth factors (9.Griendling K.K. Sorescu D. Ushio-Fukai M. Circ. Res. 2000; 86: 494-501Crossref PubMed Scopus (2625) Google Scholar). F2-isoprostanes are chemically stable prostaglandin isomers that result from non-enzymatic, free radical-mediated oxidative modification of arachidonic acid. These compounds can be found in tissues and many other body fluids including plasma and urine. These analytes have been shown to be excellent in vivo markers of oxidative stress both in human and in animal models (14.Roberts II, L.J. Morrow J.D. Free Radic. Biol. Med. 2000; 28: 505-513Crossref PubMed Scopus (863) Google Scholar). In this study, by using the LCAT ko mouse model, we tested the hypothesis that LCAT deficiency is associated with increased oxidative stress by measuring plasma levels of glycerophosphocholine-bound F2-isoprostanes (PL-F2-isoP) and vascular O2⨪ production using lucigenin-derived chemiluminescence (LDCL) in LCAT ko mice. We further studied the effect of LCAT deficiency on oxidative stress and atherosclerosis in apoE ko mice by cross-breeding the two strains. Lucigenin, NADH, CuSO4, and butylated hydroxytoluene were purchased from Sigma, and coelenterazine was purchased from Molecular Probes (Cedarlane Lab, Ontario, Canada). Free cholesterol, phospholipid, and cholesterol kits were from Wako (Neuss, Germany). Lcat−/− mice were created in Dr. Rubin's laboratory as reported previously (6.Forte T.M. Oda M.N. Knoff L. Frei B. Suh J. Harmony J.A. Stuart W.D. Rubin E.M. Ng D.S. J. Lipid Res. 1999; 40: 1276-1283Abstract Full Text Full Text PDF PubMed Google Scholar, 15.Ng D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). ApoE−/−xlcat−/− mice were generated by first cross-breeding apoE−/− mice in C57BL/6 background (The Jackson Laboratory) with lcat−/− mice to yield apoE+/−xlcat+/−. Brother-sister matings of the F1 double heterozygous siblings were carried out. ApoE−/−xlcat+/− were selected by PCR screening for subsequent serial breeding for 5 generations. All studies were carried out with the mice being fed a chow diet, and littermates were used as controls. All mouse protocols were approved by the Animal Care Committee at St. Michael's Hospital, Toronto, Canada. Plasma lipid analyses were performed on mice 7–10 weeks of age. Plasma was obtained as described previously (6.Forte T.M. Oda M.N. Knoff L. Frei B. Suh J. Harmony J.A. Stuart W.D. Rubin E.M. Ng D.S. J. Lipid Res. 1999; 40: 1276-1283Abstract Full Text Full Text PDF PubMed Google Scholar). The 1.019–1.063 g/ml (“LDL”) fraction was obtained through ultracentrifugation (16.Havel R.J. Eder H.A. Bragdon J.H. J. Clin. Invest. 1955; 34: 1345-1353Crossref PubMed Scopus (6498) Google Scholar). Fast protein liquid chromatography (FPLC) fractionation on total plasma and the LDL fraction was performed on a Superose 6HR column (10 mm J. PubMed Scopus Google Scholar). Plasma and Superose fractions were on an using for total cholesterol, and HDL cholesterol was obtained from plasma Clin. Chem. 28: PubMed Scopus Google Scholar). (PON1) activity in plasma and Superose fractions was as arylesterase activity in mice using as as described previously A. Google Scholar). from mice to weeks of was obtained by and butylated hydroxytoluene was to the plasma to a of and at The of was by high liquid chromatography with as described previously A. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The was from that of Y. K. J. 1995; PubMed Google Scholar). mice of were with of the aortic from the aortic and to the was in an in at with at by at under for with a in the at a of was and at for is reported as to a of of these coelenterazine at a of was used in of The 1.019–1.063 g/ml fraction was by ultracentrifugation of the plasma from mice weeks of for the apoE−/−xlcat+/+ and apoE−/−xlcat−/− and plasma from human This fraction was for in vitro of the LDL fraction was with 5 of in at for and the of oxidation was by at of aortic atherosclerotic lesions in mice was carried out by the Rubin E.M. J. Lipid Res. 1995; 36: Full Text PDF PubMed Google Scholar). mice in apoE ko background fed a chow were at of age. were out from the aortic to the with by with were obtained with a Ontario, Canada). The was used to the and were of The is as by of and was by were used to and was used for using the and a of was ApoE−/−xlcat+/− were used to with and The double ko mice with analyses of the LCAT-deficient mice are in The lipoprotein of the and lcat−/− mice with reported previously D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). In the apoE−/− background, LCAT deficiency the plasma We also observed an LCAT gene in the with and without the apoE−/− background. analyses on the fractions showed a of the of fractions in the apoE−/−xlcat−/− and apoE−/−xlcat+/− mice in comparison with the apoE−/− control mice was also reduced in apoE−/−xlcat−/− mouse but the lcat+/− its was also in the apoE−/−xlcat+/− mice and the other the showed a in the apoE−/−xlcat−/− mice with apoE−/−xlcat+/+ and apoE−/−xlcat+/− littermates with the of the LDL found in LCAT ko mice G. N. B. B. E. A. L.J. J. G. R. S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google and lipoproteins in from and apoE−/−xlcat−/− = = = = = = = = = = in a The total plasma PON1 arylesterase activities in are shown in A in PON1 activities was in the lcat−/− mice as with of in with (6.Forte T.M. Oda M.N. Knoff L. Frei B. Suh J. Harmony J.A. Stuart W.D. Rubin E.M. Ng D.S. J. Lipid Res. 1999; 40: 1276-1283Abstract Full Text Full Text PDF PubMed Google Scholar). in the lcat+/− mice was not of an in to the which that of the plasma the significantly lower levels in both apoE−/− and apoE−/−xlcat−/− their total plasma PON1 activities were not significantly from the apoE−/− of the PON1 activities in fractions showed that of the total plasma PON1 activity in the fractions of the apoE−/−xlcat−/− mice. A of redistribution was also observed in the plasma of apoE−/−xlcat+/− mice of the plasma in esterified to (14.Roberts II, L.J. Morrow J.D. Free Radic. Biol. Med. 2000; 28: 505-513Crossref PubMed Scopus (863) Google Scholar), the plasma of F2-isoprostanes was by measuring the of for Compared with the wild type plasma from lcat−/− mice showed a increase (p = 0.003) in plasma The lcat+/− mice showed intermediate levels but were not from of the lcat−/− mice. In apoE−/−xlcat+/+ mice showed a 2.1-fold increase (p = 0.04) in plasma as with the wild type in excellent with the increase in the plasma of as reported previously D. J. Med. 1998; PubMed Scopus Google Scholar). Surprisingly, the apoE−/−xlcat−/− mouse plasma was It is also of interest to that the of apoE−/−xlcat+/− mice was with that of the apoE−/−xlcat−/− of an We observed a the LDL fraction from apoE−/− mice and that of a human apoE−/−xlcat−/− LDL showed a of the by The of of the and the of were the two mouse strains. Vascular ring O2⨪ production was using on of mice Compared with the for lcat−/− mice was found to be increased (p = and that for lcat+/− mice 2.9-fold (p = we also observed a 2.2-fold increase (p = in of the apoE−/−xlcat+/+ mice with the mice. the for the apoE−/−xlcat−/− mice were paradoxically from the = which the normalization of the plasma in the The for apoE−/−xlcat+/− mice was found to be = This also with the PL-F2-isoprostane observed in this as The of using at high of the for superoxide and this is using coelenterazine as a E. G. R. Freeman B.A. Circ. Res. 1999; PubMed Scopus Google Scholar). All but of mice were using coelenterazine as a superoxide with in We observed a = = the and the of analyses on the showed and apoE on and PON1 activities with their respective being (p < (p = and (p < and showed an = (p = but the for PON1 activity and PON1 were and both being Aortic using the showed a = 0.02) in area in the apoE−/−xlcat−/− mice = as with the apoE−/− control = This is in with that reported by G. N. B. B. E. A. L.J. J. G. R. S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) a in background. The apoE−/−xlcat+/− = showed a 24% but was not from of the other two In this we the of in oxidative stress in lcat−/− mice using two plasma and aortic ring O2⨪ the apoE−/− mouse background, we observed a paradoxical normalization of the oxidative markers. This paradoxical was found to be associated with a retention and redistribution of PON1 arylesterase activities the fractions on Furthermore, the normalization of the oxidative markers in the mice was also found to be associated with a in atherosclerotic lesions in the male apoE−/−xlcat−/− mice as with its and apoE−/−xlcat+/+ We the first in vivo evidence a increase in plasma and aortic O2⨪ production in the lcat−/− mice. The increase is to the in an in with an in both and PON1 the two are affected in an being the in both oxidation markers in the lcat−/− mice are in the hyperlipidemic apoE−/−xlcat+/+ mice. These data suggest that the oxidative stress in the lcat−/− mice is modulated by factors plasma of the the relationship these oxidative markers and plasma PON1 activities suggest that this antioxidant plays an with the by (4.Shih D.M. Gu L. Xia Y.R. Navab M. Li W.F. Hama S. Castellani L.W. Furlong C.E. Costa L.G. Fogelman A.M. Lusis A.J. Nature. 1998; 394: 284-287Crossref PubMed Scopus (966) Google D.M. Xia Y.R. Wang X.P. Miller E. Castellani L.W. Subbanagounder G. Cheroutre H. Faull K.F. Berliner J.A. Witztum J.L. Lusis A.J. J. Biol. Chem. 2000; 275: 17527-17535Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar). The effect of the in the the of In addition to have been found to have antioxidant and is that the of HDL levels in the lcat−/− mice may also lower the activities of these and contribute to the increase in the oxidative stress has recently been in a number of species including and mouse C.E. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). This protein is in the and the and in with In vitro studies suggest that is of not the oxidized LDL but also their S.T. Ng C. Hama S. A. D.M. Lusis A.J. Navab M. Fogelman A.M. Biol. 2001; PubMed Scopus Google Scholar). its antioxidant have not been in is that the low HDL in the lcat−/− mice may be associated with a in serum levels and to the increase in oxidative stress seen in the lcat−/− mice. factor acetylhydrolase is a protein by and in both LDL and HDL in but in HDL in mice. This enzyme has the to not but also oxidized D.M. T.M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Recent studies R. B. D. A. M. G. C. M. H. D. E. 2001; PubMed Scopus Google Scholar) that of in apoE knockout mice in a in oxidized and atherosclerosis. We reported previously (6.Forte T.M. Oda M.N. Knoff L. Frei B. Suh J. Harmony J.A. Stuart W.D. Rubin E.M. Ng D.S. J. Lipid Res. 1999; 40: 1276-1283Abstract Full Text Full Text PDF PubMed Google Scholar) that activity was significantly reduced in the lcat−/− mice. the in vivo effect of deficiency in mice has not been is that a reduced plasma of activity may contribute to the oxidative The lipid of the apoE−/−xlcat+/− and apoE−/− xlcat−/− mice were both by a of the severe of the apoE−/−xlcat+/+ In the apoE ko background, the effect of on PON1 and the oxidation markers are more The gene to a of in an but has effect on PON1 activity and The in the double ko mice is the paradoxical normalization of plasma and aortic O2⨪ production in both apoE−/−xlcat+/− and apoE−/−xlcat−/− mice. the and the is = = is the redistribution of PON1 activities the fractions in the apoE−/−xlcat−/− the total PON1 activities. studies B. Biol. 2001; PubMed Scopus Google Scholar, M.C. L. R. A. M. Assmann G. G. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) in human subjects with a of HDL deficiency LCAT-deficient to redistribution of PON1 activities the A redistribution of PON1 arylesterase activity to the may be a of LCAT A by M. C. S. Biol. 1999; PubMed Scopus Google Scholar) that PON1 can to its and remains without The further that PON1 can be to these The of are not to that of lipoprotein X In apoE−/−xlcat−/− we on the of an of an and Superose in the 1.019–1.063 g/ml plasma fraction R.P. R. J. A.J. J. Clin. Invest. 1998; PubMed Google Scholar). In this plasma a but of PON1 activity with this of PON1 activity ultracentrifugation a more the data do not of PON1 with other lipoprotein the redistribution of PON1 observed be as of the for the paradoxical normalization of oxidative stress in the double knockout mice. redistribution of in LCAT-deficient mice also be In the of a redistribution of the protein to has not been to the of a for plasma C.E. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), this be with in the apoE−/−xlcat−/− mice. In is the that is associated with LDL that is It has been shown that human with the of and the mediating this are in with its from lipoproteins D.M. L.W. D. T.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). It is therefore that with in the apoE−/−xlcat−/− mice. The by which the PON1 may action is The role of PON1 oxidation of LDL has been C.E. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. R. C. R. M. J. C. C. B. Biol. 1998; PubMed Scopus Google Scholar). We observed a of the 1.019–1.063 g/ml plasma fraction from the apoE−/−xlcat−/− mice to oxidation in with the of PON1 activities with in the This is with the that the PON1 not its arylesterase activity but also its PON1 activity has been in B. S. G. D. 1997; PubMed Scopus Google Scholar), a PON1 is to its It is that the PON1 may also the the of oxidative modification in the oxidized have been shown to the oxidase (9.Griendling K.K. Sorescu D. Ushio-Fukai M. Circ. Res. 2000; 86: 494-501Crossref PubMed Scopus (2625) Google Scholar), this may the observed paradoxical normalization of O2⨪ in the apoE−/− xlcat−/− mouse The two oxidative and are both to plasma PON1 activities the on the of the two apoE on the the are as This is the result of the of apoE on the as by the on the of these two heterozygous have a relationship and in both the of on oxidative stress in heterozygous LCAT In the PON1 in the HDL and fractions are to very and their antioxidant activities may be further to the Recent studies suggest that the NAD(P)H oxidase is a major source of arterial O2⨪ T.J. West N.E. Black E. McDonald D. Ratnatunga C. Pillai R. Channon K.M. Circ. Res. 2000; 86: E85-E90Crossref PubMed Google Scholar), and oxidized LDL has been shown to be of the of this enzyme (9.Griendling K.K. Sorescu D. Ushio-Fukai M. Circ. Res. 2000; 86: 494-501Crossref PubMed Scopus (2625) Google Scholar). The and aortic O2⨪ production in the LCAT-deficient mice therefore suggests a It is that aortic wall NAD(P)H oxidase activity and oxidized may be a a for The of the apoE−/−xlcat−/− mouse LDL to oxidation may have to the of the of this and the normalization of the oxidative markers in these mice. stress has been shown to be in mouse models of atherosclerosis. In apoE ko with E in in and arterial levels in with a in aortic without the plasma cholesterol D. J. Med. 1998; PubMed Scopus Google Scholar). In the of a in aortic atherosclerosis in male apoE−/−xlcat−/− with that of and apoE−/−xlcat+/+ is in with G. N. B. B. E. A. L.J. J. G. R. S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) a in we found a in plasma and LDL levels in apoE−/−xlcat−/− the is to for the normalization of the aortic O2⨪ Our data therefore suggest that the increased of the LDL to oxidative modification in the apoE−/−xlcat−/− mice is for the observed in atherosclerotic and this may in be a result of the retention and redistribution of PON1 in the hyperlipidemic LCAT-deficient mice. Furthermore, the in the plasma PON1 activities and the oxidative stress markers in the heterozygous LCAT-deficient mice suggests that the role of the including in atherosclerosis is in LCAT We the excellent of and

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