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The advanced atherosclerotic lesion is characterized by the formation of microscopic cholesterol crystals that contribute to mechanisms of inflammation and apoptotic cell death. These crystals develop from membrane cholesterol domains, a process that is accelerated under conditions of hyperlipidemia and oxidative stress. In this study, the comparative effects of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on oxidative stress-induced cholesterol domain formation were tested in model membranes containing physiologic levels of cholesterol using small angle x-ray diffraction approaches. In the absence of HMG-CoA reductase, only the atorvastatin active o-hydroxy metabolite (ATM) blocked membrane cholesterol domain formation as a function of oxidative stress. This effect of ATM is attributed to electron donation and proton stabilization mechanisms associated with its phenoxy group located in the membrane hydrocarbon core. ATM inhibited lipid peroxidation in human low density lipoprotein and phospholipid vesicles in a dose-dependent manner, unlike its parent and other statins (pravastatin, rosuvastatin, simvastatin). These findings indicate an atheroprotective effect of ATM on membrane lipid organization through a potent antioxidant mechanism. The advanced atherosclerotic lesion is characterized by the formation of microscopic cholesterol crystals that contribute to mechanisms of inflammation and apoptotic cell death. These crystals develop from membrane cholesterol domains, a process that is accelerated under conditions of hyperlipidemia and oxidative stress. In this study, the comparative effects of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on oxidative stress-induced cholesterol domain formation were tested in model membranes containing physiologic levels of cholesterol using small angle x-ray diffraction approaches. In the absence of HMG-CoA reductase, only the atorvastatin active o-hydroxy metabolite (ATM) blocked membrane cholesterol domain formation as a function of oxidative stress. This effect of ATM is attributed to electron donation and proton stabilization mechanisms associated with its phenoxy group located in the membrane hydrocarbon core. ATM inhibited lipid peroxidation in human low density lipoprotein and phospholipid vesicles in a dose-dependent manner, unlike its parent and other statins (pravastatin, rosuvastatin, simvastatin). These findings indicate an atheroprotective effect of ATM on membrane lipid organization through a potent antioxidant mechanism. The unstable atherosclerotic lesion is characterized by extracellular lipid deposits consisting of cholesterol (both free and esterified), phospholipids, and lesser amounts of triacylglycerol (1Small D.M. Arteriosclerosis. 1988; 8: 103-129Crossref PubMed Google Scholar). Free cholesterol is associated with phospholipid membranes and insoluble, extracellular crystals in the lipid core of the plaque. Membrane-associated cholesterol crystals have been characterized in cell culture systems and tissue explants from animal models of atherosclerosis using electron microscopy and x-ray diffraction approaches (2Tulenko T.N. Chen M. Mason P.E. Mason R.P. J. Lipid Res. 1998; 39: 947-956Abstract Full Text Full Text PDF PubMed Google Scholar, 3Phillips J.E. Geng Y.J. Mason R.P. Atherosclerosis. 2001; 159: 125-135Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Microscopic cholesterol crystalline structures have also been observed in macrophage foam cells following treatment with LDL 2The abbreviations used are: LDL, low density lipoprotein; ATM, atorvastatin hydroxy metabolite; PUFA, polyunsaturated fatty acid; MDA, malondialdehyde; TBA, thiobarbituric acid; TBARS, thiobarbituric acid reactive substances; DAPC, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine; DLPC, 1,2-dilinoleoyl-sn-glycero-3-phosphocholine; LOOH, lipid hydroperoxide(s); MLV, multilamellar lipid vesicle; GC, gas chromatography; MS, mass spectrometry; C/P, cholesterol-to-phospholipid; HMG, hydroxymethylglutaryl. or by inhibition of acyl-coenzyme A:cholesterol acyltransferase (4Kellner-Weibel G. Yancey P.G. Jerome W.G. Walser T. Mason R.P. Phillips M.C. Rothblat G.H. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1891-1898Crossref PubMed Scopus (135) Google Scholar, 5Geng Y.J. Phillips J.E. Mason R.P. Casscells S.W. Biochem. Pharmacol. 2003; 66: 1485-1492Crossref PubMed Scopus (41) Google Scholar, 6Kellner-Weibel G. Jerome W.G. Jones N.L. Small D.M. Warner G.J. Stoltenborg J.K. Kearney M.A. Corjay M.H. Phillips M.C. Rothblat G.H. Arterioscler. Thromb. Vasc. Biol. 1998; 18: 423-431Crossref PubMed Scopus (140) Google Scholar). These crystalline structures contribute to mechanisms of cell death and inflammation (3Phillips J.E. Geng Y.J. Mason R.P. Atherosclerosis. 2001; 159: 125-135Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 4Kellner-Weibel G. Yancey P.G. Jerome W.G. Walser T. Mason R.P. Phillips M.C. Rothblat G.H. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1891-1898Crossref PubMed Scopus (135) Google Scholar, 5Geng Y.J. Phillips J.E. Mason R.P. Casscells S.W. Biochem. Pharmacol. 2003; 66: 1485-1492Crossref PubMed Scopus (41) Google Scholar). Although non-crystalline membrane cholesterol can readily exchange from the plaque with plasma lipoprotein particles, cholesterol in the crystalline state is insoluble and does not respond to pharmacologic intervention or reverse cholesterol transport mechanisms (1Small D.M. Arteriosclerosis. 1988; 8: 103-129Crossref PubMed Google Scholar). We have recently reported that oxidative stress, a pathologic process associated with cardiovascular risk factors (e.g. hypertension, diabetes, hypercholesterolemia) (7Madamanchi N.R. Vendrov A. Runge M.S. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 29-38Crossref PubMed Scopus (71) Google Scholar), contributes directly to the formation of cholesterol crystalline microdomains in membranes (8Jacob R.F. Mason R.P. J. Biol. Chem. 2005; 280: 39380-39387Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Domain formation as a function of lipid peroxidation was observed in lipid vesicles containing physiologic levels of cholesterol using small angle x-ray diffraction approaches (2Tulenko T.N. Chen M. Mason P.E. Mason R.P. J. Lipid Res. 1998; 39: 947-956Abstract Full Text Full Text PDF PubMed Google Scholar, 9Jacob R.F. Cenedella R.J. Mason R.P. J. Biol. Chem. 1999; 274: 31613-31618Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). These observations have led to our current hypothesis that the active o-hydroxy metabolite of atorvastatin (ATM) may interfere with cholesterol domain formation without altering membrane cholesterol content. ATM was selected as it has potent antioxidant activity, independent of HMG-CoA reductase inhibition (10Aviram M. Rosenblat M. Bisgaier C.L. Newton R.S. Atherosclerosis. 1998; 138: 271-280Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 11Mason R.P. Walter M.F. Jacob R.F. Circulation. 2004; 109: II34-II41Crossref PubMed Google Scholar). In randomized clinical trials, atorvastatin treatment has been shown to have anti-inflammatory and antioxidant benefits (12Nissen S.E. Tuzcu E.M. Schoenhagen P. Crowe T. Sasiela W.J. Tsai J. Orazem J. Magorien R.D. O'Shaughnessy C. Ganz P. N. Engl. J. Med. 2005; 352: 29-38Crossref PubMed Scopus (1186) Google Scholar, 13Ridker P.M. Cannon C.P. Morrow D. Rifai N. Rose L.M. McCabe C.H. Pfeffer M.A. Braunwald E. N. Engl. J. Med. 2005; 352: 20-28Crossref PubMed Scopus (1991) Google Scholar, 14Tsimikas S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. Circulation. 2004; 110: 1406-1412Crossref PubMed Scopus (188) Google Scholar, 15Shishehbor M.H. Brenna M.L. Aviles R.J. Fu X. Penn M.S. Sprecher D.L. Hazen S.L. Circulation. 2003; 108: 426-431Crossref PubMed Scopus (363) Google Scholar) and is associated with reduced risk and progression of cardiovascular disease (16Cannon C.P. Braunwald E. McCabe C.H. N. Engl. J. Med. 2004; 350: 1495-1504Crossref PubMed Scopus (4352) Google Scholar, 17Nissen S.E. Tuzcu E.M. Schoenhagen P. Brown B.G. Ganz P. Vogel R.A. Crowe T. Howard G. Cooper C.J. Brodie B. Grines C.L. DeMaria A.N. J. Am. Med. Assoc. 2004; 291: 1071-1080Crossref PubMed Scopus (2101) Google Scholar, 18Sever P.S. Dahlof B. Poulter N.R. Lancet. 2003; 361: 1149-1158Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar). In this study, the activity of ATM was compared with other statins (pravastatin, rosuvastatin, simvastatin) and known antioxidants (probucol, Trolox) using membranes enriched with polyunsaturated fatty acids (PUFAs) and physiologic levels of cholesterol (17-37.5 mol %) (19Emmelot P. Jamieson G.A. Robinson D.M. Mammalian Cell Membranes. 2. Butterworths, Boston, MA1977: 1-54Google Scholar, 20Houslay M.D. Stanley K.K. Dynamics of Biological Membranes: Influence on Synthesis, Structure and Function. John Wiley 234: 620-630Crossref PubMed Scopus (60) Google Scholar). The concentration of MDA was confirmed based on a standard curve for MDA·TBA complex using 1,1,3,3-tetramethoxypropane after acid hydrolysis. In these assays, LDL was incubated for 30 min with vehicle or ATM. The oxidation reaction was initiated by the addition of 10 μm CuSO4 at 37 °C. For measurement of TBARS, 100 μl of sample was removed after 2 h and combined with 1 ml of 0.5% TBA, 10 μl of 5% trichloroacetic acid, and aliquots of EDTA and butylated hydroxytoluene to produce a final concentration of 20 μm for each. After incubation at 100 °C for 30 min, the samples were cooled, and the absorbances were measured at 532 nm to calculate TBARS levels. The for TBARS is Preparation of Lipid for Lipid Peroxidation and lipid peroxidation and x-ray diffraction were from phospholipid and cholesterol at of lipid were to and under a of gas for was removed under in low Lipid samples were in diffraction and was at to form as J. Biol. PubMed Scopus Google Scholar). Determination of by with are from the formation of of acid, to and to levels of were measured in from in the of vehicle or statins and using with chemical as by Walter M.F. G.G. G.J. Biochem. 280: PubMed Scopus (71) Google Scholar). were to for h at 37 and peroxidation was by the addition of 25 μl of EDTA and 20 μl of butylated formation was analyzed in samples by mass in the Boston, Lipid in these μl of from was in diffraction in the absence and of ATM or at The vesicles were in a at 37 °C and to peroxidation without the of After a incubation to for aliquots of the samples were and the peroxidation reaction was by the addition of 25 μl of EDTA and 20 μl of butylated The of lipid peroxidation in the samples was measured by the M. M. M. G. J. Lipid Res. Full Text PDF PubMed Google Scholar). The is based on the measurement of has a of at The of is directly to the of lipid that is in the process of lipid ml of was to by incubation in the absence of for absorbances were measured at Lipid concentration were as Preparation of for Small effect of lipid peroxidation on cholesterol crystalline formation was measured in from and cholesterol at The final phospholipid concentration was and the of was and The of was in low final that and by were for diffraction by in a at for 50 min at °C. were in in and were as in Mason R.P. J. Full Text PDF PubMed Scopus Google Scholar). The of the lipid vesicles was analyzed by electron microscopy and shown to form stable lipid Small of Lipid and Domain angle x-ray diffraction approaches were used to the effects of oxidative on membrane and the of diffraction experiments were by the samples at with to a x-ray In addition to of the cholesterol crystals were used to the and of the as R.P. J. Full Text PDF PubMed Scopus Google Scholar). The cell of the membrane lipid was using diffraction obtained from samples in this study were analyzed using to electron density membrane lipid of membrane diffraction was R.P. J. Full Text PDF PubMed Scopus Google Scholar). are as The of results from independent conditions in was tested using the and inhibition or of with effects of ATM on and TBARS in and LDL, of was of on of diffraction of membrane vesicles consisting of phospholipid and cholesterol produced and diffraction that to structures in the membrane (e.g. cholesterol domains, as shown in Fig. 2. The measurement to the of the with a of 1 or Although a phospholipid has a of on of cholesterol the cholesterol crystalline domain has a of a cholesterol has a of PubMed Scopus Google Scholar, G.G. J. Full Text PDF PubMed Scopus Google Scholar). a function of lipid peroxidation in with DAPC, observed in the and organization of the formation of cholesterol crystalline and reduced membrane Following lipid peroxidation in vesicles containing low cholesterol was for of cholesterol crystalline microdomains that as as h the samples after a The of the cholesterol domain that the a was and by in sample or In addition to the formation of cholesterol crystalline domains, lipid peroxidation produced a in the of the membrane as a function of a for the membrane was reduced from to following oxidative stress. This in membrane was by a in cholesterol domain was of phospholipid to to the phospholipid The of cholesterol in the membranes also domain After for cholesterol was observed at a at a cholesterol were observed as as h not an the effects of oxidative on membrane lipid vesicles in the absence and of cholesterol levels. The membrane samples without cholesterol were with as by a membrane of only these samples not of of after h of lipid the absence of cholesterol domains, was a in membrane of these samples to oxidative to the phospholipid not of ATM, and on Domain the formation of cholesterol was attributed to oxidative stress, tested the effect of and antioxidants on lipid ATM has been shown to have potent antioxidant activity, as compared with the parent (10Aviram M. Rosenblat M. Bisgaier C.L. Newton R.S. Atherosclerosis. 1998; 138: 271-280Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). In this study, inhibition of cholesterol formation was by membranes with of ATM, as compared with ATM domain formation was not observed for h until the concentration of the was reduced to 2 mol other statins effect on cholesterol crystalline domain formation under conditions In cholesterol formation was not inhibited by was blocked by the The comparative effects of these on cholesterol are in Fig. of of the diffraction was used to produce a electron density of the membrane lipid of electron density of the electron density to the of the phospholipid of electron density associated with the of the phospholipid was also to the of to and low electron density were directly from samples to calculate the of in the In membranes from and the addition of ATM produced a in electron density in the membrane hydrocarbon core with a of from the hydrocarbon core This is with ATM and the phospholipid these findings that the of ATM the hydrocarbon to the This membrane of ATM may for to the HMG-CoA reductase this membrane the o-hydroxy in the of the of the phospholipid it may in proton donation mechanisms to the of free the membrane for the was to the of the membrane with a from ATM on these a membrane for ATM that its phenoxy group in to the of the of structures with lipid A. 2003; PubMed Scopus Google Scholar), other may ATM in are that can by free of acid associated with phospholipid in LDL and These of oxidative contribute to and are associated with the atherosclerotic plaque Morrow Free Biol. Med. PubMed Scopus Google Scholar, D. A. J. J. G.A. J. PubMed Scopus Google Scholar). We tested the effect of ATM on peroxidation of lipid vesicles enriched with acid (DAPC), the for formation of The results of this that the addition of ATM at 100 nm reduced levels by as compared with to was not a in levels in samples with or was a in levels with atorvastatin parent by it was not levels of the reactive MDA, were reduced in the of ATM by from to μm at 37 inhibition was not observed for atorvastatin parent and other statins not ATM Lipid Peroxidation in LDL and tested the dose-dependent effects of ATM on peroxidation in enriched with and human ATM inhibited oxidation in lipid vesicles a of nm through to pharmacologic was a dose-dependent in an of as a function of ATM The for ATM in the samples was with at a concentration as low as 100 nm a of that pharmacologic conditions nm through ATM a and dose-dependent in TBARS levels in human LDL TBARS levels indicate the of reactive as MDA, an of LDL the tested ATM produced an in LDL as compared with of in comparative antioxidant effects of and ATM were tested in as a function of cholesterol content. We have shown in animal that the in animal tissue under conditions of hyperlipidemia (2Tulenko T.N. Chen M. Mason P.E. Mason R.P. J. Lipid Res. 1998; 39: 947-956Abstract Full Text Full Text PDF PubMed Google Scholar). This in cell plasma membrane cholesterol may have effects on protein function and directly the effect of cholesterol on antioxidant the activity of in lipid vesicles with of cholesterol and shown in Fig. was a the of to lipid formation and the in the lipid The inhibition of from at a to and at of and the inhibition of with ATM at the of at a as as The other statins tested (pravastatin, or an not formation in these lipid vesicles not antioxidant effects of ATM and in membranes enriched with ATM and at were incubated with lipid vesicles containing a of of Peroxidation of in the absence of at 37 °C for levels of were measured by the based on the measurement of The of is directly to the of that is in the are vehicle or The from this study was that the ATM inhibited in membrane lipid and cholesterol domain following oxidative stress. The effects of ATM were attributed to antioxidant activity and observed in membrane samples containing physiologic levels of and phospholipid with of the membrane the of membrane cholesterol crystalline In addition to with cholesterol ATM reduced in membrane associated with lipid The antioxidant activity of ATM is attributed to electron donation and proton stabilization mechanisms associated with its phenoxy group located in the membrane hydrocarbon core. effect was observed with a that the of ATM in the membrane not other statins that not this membrane (e.g. or phenoxy This may an atheroprotective for ATM as formation of cholesterol crystals contributes to mechanisms of cell death and inflammation (3Phillips J.E. Geng Y.J. Mason R.P. Atherosclerosis. 2001; 159: 125-135Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 4Kellner-Weibel G. Yancey P.G. Jerome W.G. Walser T. Mason R.P. Phillips M.C. Rothblat G.H. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1891-1898Crossref PubMed Scopus (135) Google Scholar, 5Geng Y.J. Phillips J.E. Mason R.P. Casscells S.W. Biochem. Pharmacol. 2003; 66: 1485-1492Crossref PubMed Scopus (41) Google Scholar) these crystals not respond to pharmacologic intervention or reverse cholesterol transport These findings that oxidative of phospholipid the organization of cholesterol crystalline in lipid vesicles containing or low cholesterol levels (8Jacob R.F. Mason R.P. J. Biol. Chem. 2005; 280: 39380-39387Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). The for this effect on cholesterol is attributed to a in from oxidative to a and of of membrane phospholipid is a free reaction by is the following of a from the These chemical the of the phospholipid with other lipid as with phospholipids, containing and fatty S. Phillips M.C. 1988; PubMed Scopus Google Scholar). of cholesterol domain formation in vesicles enriched with other phospholipid containing (e.g. are as a function of oxidative stress. In addition to the formation of cholesterol crystalline domains, observed that oxidative to the membrane a and in membrane This is attributed to chemical of the lipid reactive as cholesterol was these crystalline the of cholesterol in the phospholipid in in the phospholipid and reduced membrane These findings are with that have an for cholesterol in membrane and lipid for function (2Tulenko T.N. Chen M. Mason P.E. Mason R.P. J. Lipid Res. 1998; 39: 947-956Abstract Full Text Full Text PDF PubMed Google Scholar, Mason R.P. J. Biol. PubMed Scopus Google Scholar). a in membrane to have effects on for transport and other in Mason R.P. J. Biol. PubMed Scopus Google Scholar, M. Mason R.P. T.N. PubMed Scopus (71) Google Scholar). 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Lancet. 2003; 361: 1149-1158Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar). reported in the Scholar), of the atorvastatin is in the in the form of hydroxy that are active inhibitors of HMG-CoA other ATM has the activity as its Atorvastatin treatment has been used to the risk and progression of cardiovascular disease (16Cannon C.P. Braunwald E. McCabe C.H. N. Engl. J. Med. 2004; 350: 1495-1504Crossref PubMed Scopus (4352) Google Scholar, 17Nissen S.E. Tuzcu E.M. Schoenhagen P. Brown B.G. Ganz P. Vogel R.A. Crowe T. Howard G. Cooper C.J. Brodie B. Grines C.L. DeMaria A.N. J. Am. Med. Assoc. 2004; 291: 1071-1080Crossref PubMed Scopus (2101) Google Scholar, 18Sever P.S. Dahlof B. Poulter N.R. Lancet. 2003; 361: 1149-1158Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar), is also clinical that this has anti-inflammatory and antioxidant that may not to LDL (12Nissen S.E. Tuzcu E.M. Schoenhagen P. Crowe T. Sasiela W.J. Tsai J. Orazem J. Magorien R.D. O'Shaughnessy C. Ganz P. N. Engl. J. Med. 2005; 352: 29-38Crossref PubMed Scopus (1186) Google Scholar, 13Ridker P.M. Cannon C.P. Morrow D. Rifai N. Rose L.M. McCabe C.H. Pfeffer M.A. Braunwald E. N. Engl. J. Med. 2005; 352: 20-28Crossref PubMed Scopus (1991) Google Scholar, 14Tsimikas S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. Circulation. 2004; 110: 1406-1412Crossref PubMed Scopus (188) Google Scholar, 15Shishehbor M.H. Brenna M.L. Aviles R.J. Fu X. Penn M.S. Sprecher D.L. Hazen S.L. Circulation. 2003; 108: 426-431Crossref PubMed Scopus (363) Google Scholar). small clinical study that measured protein oxidation (e.g. that treatment with atorvastatin a in these oxidation in oxidation were observed at its M.H. Brenna M.L. Aviles R.J. Fu X. Penn M.S. Sprecher D.L. Hazen S.L. Circulation. 2003; 108: 426-431Crossref PubMed Scopus (363) Google Scholar). In a study of treatment with a of atorvastatin a in levels of on after a S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. Circulation. 2004; 110: 1406-1412Crossref PubMed Scopus (188) Google Scholar). the effects of atorvastatin other statins on of oxidative are and this of
Mason et al. (Wed,) studied this question.