Constitutive inhibition of plasma CETP by apolipoprotein C1 is blunted in dyslipidemic patients with coronary artery disease

Abstract

Plasma cholesteryl ester transfer protein (CETP) promotes the cholesterol enrichment of apoB-containing lipoproteins (VLDL and LDL) at the expense of HDL. Recent studies demonstrated that apoC1 is a potent CETP inhibitor in plasma of healthy, normolipidemic subjects. Our goal was to establish whether the modulation of CETP activity by apoC1 is influenced by dyslipidemia in patients with documented coronary artery disease (CAD). In the total CAD population studied (n = 240), apoC1 levels correlated negatively with CETP activity, independently of apoE-epsilon, CETP-Taq1B, and apoC1-Hpa1 genotypes. In multivariate analysis, the negative relationship was observed only in normolipidemic patients, not in those with hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia. In the normolipidemic subjects, apoC1 levels were positively associated with higher HDL- to LDL-cholesterol ratio (r = 0.359, P < 0.001). It is concluded that apoC1 as a CETP inhibitor no longer operates on cholesterol redistribution in high-risk patients with dyslipidemia, probably due to increasing amounts of VLDL-bound apoC1, which is inactive as a CETP inhibitor. Patients with dyslipidemia could experience major benefits from treatment with pharmacological CETP inhibitors, which might compensate for blunted endogenous inhibition. Plasma cholesteryl ester transfer protein (CETP) promotes the cholesterol enrichment of apoB-containing lipoproteins (VLDL and LDL) at the expense of HDL. Recent studies demonstrated that apoC1 is a potent CETP inhibitor in plasma of healthy, normolipidemic subjects. Our goal was to establish whether the modulation of CETP activity by apoC1 is influenced by dyslipidemia in patients with documented coronary artery disease (CAD). In the total CAD population studied (n = 240), apoC1 levels correlated negatively with CETP activity, independently of apoE-epsilon, CETP-Taq1B, and apoC1-Hpa1 genotypes. In multivariate analysis, the negative relationship was observed only in normolipidemic patients, not in those with hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia. In the normolipidemic subjects, apoC1 levels were positively associated with higher HDL- to LDL-cholesterol ratio (r = 0.359, P < 0.001). It is concluded that apoC1 as a CETP inhibitor no longer operates on cholesterol redistribution in high-risk patients with dyslipidemia, probably due to increasing amounts of VLDL-bound apoC1, which is inactive as a CETP inhibitor. Patients with dyslipidemia could experience major benefits from treatment with pharmacological CETP inhibitors, which might compensate for blunted endogenous inhibition. Large cohort studies have indicated that the risk for cardiovascular disease correlates positively with the cholesterol content of apoB-containing lipoproteins (VLDL and LDL) but negatively with the cholesterol content of HDL (1.Gotto Jr, A.M. Brinton E.A. Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update.J. Am. Coll. Cardiol. 2004; 43: 717-724Crossref PubMed Scopus (203) Google Scholar). Thus, interest in intervention strategies that lead not only to a significant reduction in LDL-cholesterol (LDL-C) but also to a concomitant increase in HDL-cholesterol (HDL-C) has grown in recent years. In this context, particular attention has been paid to the inhibition of cholesteryl ester transfer protein (CETP) because this factor promotes the cholesterol enrichment of apoB-containing lipoproteins at the expense of HDL (2.Barter P.J. Brewer Jr, H.B. Chapman M.J. Hennekens C.H. Rader D.J. Tall A.R. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 160-167Crossref PubMed Scopus (708) Google Scholar). High CETP activity was found to accelerate the progression of atherosclerosis and to increase the incidence of coronary artery disease (3.Boekholdt S.M. Kuivenhoven J.A. Wareham N.J. Peters R.J. Jukema J.W. Luben R. Bingham S.A. Day N.E. Kastelein J.J. Khaw K.T. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study.Circulation. 2004; 110: 1418-1423Crossref PubMed Scopus (188) Google Scholar–6.Zeller M. Masson D. Farnier M. Lorgis L. Deckert V. Pais de Barros J.P. Desrumaux C. Sicard P. Grober J. Blache D. et al.High serum cholesteryl ester transfer rates and small high-density lipoproteins are associated with young age in patients with acute myocardial infarction.J. Am. Coll. Cardiol. 2007; 50: 1948-1955Crossref PubMed Scopus (52) Google Scholar). Recent intervention trials of secondary prevention in high-risk patients confirmed that pharmacological inhibition of CETP leads to a marked, unrivalled rise in the HDL-C to LDL-C ratio (7.Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. et al.Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2602) Google Scholar, 8.Cannon C.P. Dansky H.M. Davidson M. Gotto Jr, A.M. Brinton E.A. Gould A.L. Stepanavage M. Liu S.X. Shah S. Rubino J. et al.Design of the DEFINE trial: determining the efficacy and tolerability of CETP inhibition with anacetrapib.Am. Heart J. 2009; 158: 513-519.e3Crossref PubMed Scopus (79) Google Scholar–9.Cannon C.P. Shah S. Dansky H.M. Davidson M. Brinton E.A. Gotto A.M. Stepanavage M. Liu S.X. Gibbons P. Ashraf T.B. et al.Safety of anacetrapib in patients with or at high risk for coronary heart disease.N. Engl. J. Med. 2010; 363: 2406-2415Crossref PubMed Scopus (679) Google Scholar). Although the outcome of the ILLUMINATE study was negative, probably because of an off-site target effect of the CETP inhibitor torcetrapib, treatments with anacetrapib in the DEFINE study (9.Cannon C.P. Shah S. Dansky H.M. Davidson M. Brinton E.A. Gotto A.M. Stepanavage M. Liu S.X. Gibbons P. Ashraf T.B. et al.Safety of anacetrapib in patients with or at high risk for coronary heart disease.N. Engl. J. Med. 2010; 363: 2406-2415Crossref PubMed Scopus (679) Google Scholar) and dalcetrapib in the dal-PLAQUE study (10.Fayad Z.A. Mani V. Woodward M. Kallend D. Abt M. Burgess T. Fuster V. Ballantyne C.M. Stein E.A. Tardif J.C. et al.Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.Lancet. 2011; 378: 1547-1559Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar) did not result in adverse cardiovascular effects. Thus, prevention of cardiovascular disease with pharmacological CETP inhibitors is still worthwhile to pursue, and whether CETP inhibition might be equally relevant in subgroups of high-risk patients with distinct lipoprotein profiles remains an unanswered question. Unlike apoB-containing lipoproteins, HDL was found in earlier studies to inhibit CETP activity in a concentration-dependent manner (11.Barter P.J. Jones M.E. Kinetic studies of the transfer of esterified cholesterol between human plasma low and high density lipoproteins.J. Lipid Res. 1980; 21: 238-249Abstract Full Text PDF PubMed Google Scholar). In subsequent studies, and among all the apolipoprotein components of HDL, apoC1 arose as a potent inhibitor of CETP in T. Masson D. de Barros J.P. P. D. L. apolipoprotein for the of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). apoC1, was as a potent CETP inhibitor in and of transfer inhibitor protein with apolipoprotein Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the transfer activity of apoC1 that is associated with the plasma HDL T. Masson D. de Barros J.P. P. D. L. apolipoprotein for the of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein Biol. Full Text Full Text PDF PubMed Scopus Google effect in and of transfer inhibitor protein with apolipoprotein Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). human apoC1 inhibitor operates the of the HDL which is as a major of the of the and of L. T. de Barros J.P. Blache D. P. J. J.C. P. Masson D. et of the of plasma cholesteryl ester transfer protein by inhibitor apolipoprotein Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Barros J.P. T. L. Masson D. L. is a of cholesteryl ester transfer protein activity in human but not in Lipid Res. 2009; 50: Full Text Full Text PDF PubMed Scopus Google Scholar). in CETP and human apoC1 CETP to earlier in with human apoC1 T. Masson D. L. Deckert V. Pais de Barros J.P. L. et plasma lipoprotein by human cholesteryl ester transfer protein (CETP) in CETP Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, T. Masson D. Pais de Barros J.P. L. Deckert V. L. et is not a relevant to cholesteryl ester transfer protein (CETP) activity in CETP J. PubMed Scopus Google Scholar). In no of apoC1 have been In healthy subjects, plasma apoC1 was to negatively with cholesteryl ester transfer activity on the Barros J.P. T. L. Masson D. L. is a of cholesteryl ester transfer protein activity in human but not in Lipid Res. 2009; 50: Full Text Full Text PDF PubMed Scopus Google and positively with HDL-C on the de D. Plasma apolipoprotein from in Biol. Med. PubMed Scopus Google Scholar, L. of and in from men and to serum lipoprotein PubMed Scopus Google Scholar). the of apoC1 on CETP activity and HDL levels was not in and for HDL-C as as HDL-C to LDL-C ratio because of the of CETP activity remains to be whether apoC1 still a potent effect on CETP in patients is of the study was to the of plasma apoC1 as a CETP inhibitor in and patients with documented coronary artery disease and to the in of cholesterol between HDL and apoB-containing and patients of a from to at the in for the of acute myocardial or coronary artery patients were found to have at significant coronary on was on the of a and myocardial or of the CAD was on Patients with documented were patients were of age and and for to be in a with the of and by the clinical and were and clinical were of the CAD patients were for at patients were for and all of and and increase in the of was on the of a of or a of or or a of treatment R. R. A.M. S. et for the of the for the of of the of and of the of Heart J. 2007; Google Scholar). was by in by the of in of patients were normolipidemic because of or the of dyslipidemia was of was as plasma LDL-C higher was as a plasma higher and combined was as a plasma LDL-C higher and a plasma higher on and of High in of the on and of High in PubMed Scopus Google Scholar). and apoC1 studies, an group of healthy was are in were by a at = in a in a and and HDL. were to apoC1 were for serum the of were and at was from of a with a to the serum cholesterol and HDL-C levels were using LDL-C was by the were and was by a from were was in total plasma and in lipoprotein by a using an apoC1 from D. T. Pais de Barros J.P. P. L. Masson D. plasma apolipoprotein a for lipoprotein 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). and was by a as D.J. D. J. of plasma HDL cholesterol and by and between the in the CETP and and Thromb. PubMed Scopus Google Scholar, by the Res. PubMed Scopus Google Scholar, L. R. R. C. S. T. of apolipoprotein and an distinct of with the of apolipoprotein Lipid Res. Full Text Full Text PDF PubMed Google of human apolipoprotein by and with Lipid Res. Full Text PDF PubMed Google Scholar). was using the the in of the CETP and the in the of the and and in the of the and of of and of in a total of was for of at at and at with an of at of was with of the for CETP for and for to the of the for CETP and were on a and with analysis, were on an and with of indicated the of the in the CETP of and indicated the of the and of and indicated for the of for to and in and in or in and in on the of the in of potent are on the of which are in distinct of a of to the a of to the and of the of and to the cholesteryl ester transfer in plasma was the transfer from HDL endogenous apoB-containing lipoproteins M. Masson D. Farnier M. Lorgis L. Deckert V. Pais de Barros J.P. Desrumaux C. Sicard P. Grober J. Blache D. et al.High serum cholesteryl ester transfer rates and small high-density lipoproteins are associated with young age in patients with acute myocardial infarction.J. Am. Coll. Cardiol. 2007; 50: 1948-1955Crossref PubMed Scopus (52) Google Scholar). CETP was by a with V. L. P. C. of the human cholesteryl ester transfer protein PubMed Scopus Google Scholar). CETP activity were as the ratio of the plasma cholesteryl ester transfer to the plasma CETP and was as of of CETP are as or as between were by the for and by the for between CETP activity and apoC1 were by or multivariate analysis, with as P < was indicated in the age of the study population was and were of the patients with hypercholesterolemia, with hypertriglyceridemia, with combined and with were and patients were with hypercholesterolemia, combined or and patients with myocardial of total population (n = and of normolipidemic patients and = = = = = from P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from hypertriglyceridemia, P < and P < from P < P < and P < inhibitor or from P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from hypertriglyceridemia, P < and P < cholesterol from P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from hypertriglyceridemia, P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from hypertriglyceridemia, P < and P < from P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from hypertriglyceridemia, P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from hypercholesterolemia, P < P < and P < from P < P < and P < from P < P < and P < from P < P < and P < activity from P < P < and P < from P < P < and P < are from P < P < and P < from hypercholesterolemia, P < P < and P < from hypertriglyceridemia, P < and P < in a are In a to the relationship between apoC1 and CETP activity, apoC1 and CETP activity levels were in plasma from patients with documented in a negative was observed between plasma apoC1 and CETP activity in CAD patients (r = P < = 240), the relationship was that earlier by the using the in healthy, normolipidemic Barros J.P. 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T. Pais de Barros J.P. P. L. Masson D. plasma apolipoprotein a for lipoprotein 2007; Full Text Full Text PDF PubMed Scopus Google but not with total that of in to the of the inhibition of CETP activity in dyslipidemia between apoC1 levels in and in total plasma and plasma levels in a group of healthy subjects. was by as in and in total plasma and in were by a as in and of healthy are in were by between total apoC1 and = P < Large in a significant between apoC1 and HDL-C levels was observed in the total population (r = P < 0.001). was in the normolipidemic patients (r = P < but still was observed in patients (r = P < in with the normolipidemic no was observed between plasma apoC1 levels and the HDL-C to LDL-C ratio Plasma apoC1 levels were associated with HDL-C levels with the HDL-C to LDL-C ratio in patients with or combined and was associated not with LDL-C in all subgroups and might in the of apoC1 in the of increasing amounts of cholesterol in apoB-containing lipoproteins Desrumaux C. D.J. 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Full Text Full Text PDF PubMed Scopus Google between plasma apoC1 and total plasma and ratio in normolipidemic and in (n = cholesterol (n = cholesterol (n = cholesterol (n = cholesterol significant are with in a significant are with In multivariate analysis, for for and for apoC1, a significant of apoC1 to HDL-C levels was observed in the normolipidemic only Plasma and CETP were in subgroups of patients with low high apoC1 on the of the In the total was no between the high and low apoC1 subgroups with to CETP but CETP activity was in patients with apoC1 with patients with apoC1 P < HDL-C levels for the higher total cholesterol levels in patients with high apoC1 normolipidemic patients, CETP activity P < higher HDL-C P < and higher HDL-C to LDL-C ratio P < were observed with apoC1 the in plasma lipoprotein and cholesterol in normolipidemic patients in the of in total plasma and CETP patients, higher total cholesterol levels P < CETP activity P < and no significant in HDL-C and in the HDL-C to LDL-C ratio were observed in the high apoC1 patients with or combined no significant in CETP activity or in the lipoprotein of cholesterol were observed patients with plasma apoC1 of to the of apoC1 in total population or subgroups of normolipidemic and = = = = = = = = = = < for apoC1 apoC1 the cholesterol < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the LDL-C < for apoC1 apoC1 the activity < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the < for apoC1 apoC1 the for apoC1 was are significant are with P < for apoC1 apoC1 the P < for apoC1 apoC1 the in a for apoC1 was are significant are with is a apolipoprotein that is by the It is to the as a of lipoproteins M. 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PubMed Scopus Google Scholar, L. of and in from men and to serum lipoprotein PubMed Scopus Google Scholar). of apoC1 to CETP activity as a to the transfer of cholesteryl from HDL and has been documented earlier in higher CETP activity T. Masson D. L. Deckert V. Pais de Barros J.P. L. et plasma lipoprotein by human cholesteryl ester transfer protein (CETP) in CETP Biol. Full Text Full Text PDF PubMed Scopus Google and in CETP activity T. Masson D. Pais de Barros J.P. L. Deckert V. L. et is not a relevant to cholesteryl ester transfer protein (CETP) activity in CETP J. PubMed Scopus Google with a negative between plasma of apoC1 and levels of CETP activity was in healthy, normolipidemic Barros J.P. T. L. Masson D. 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In the CETP effect of apoC1 might to effect on plasma cholesterol higher HDL-C to LDL-C ratio the of an CETP activity was in the study in normolipidemic patients with high low plasma apoC1 the study in patients with CAD to the of the of human apoC1, the modulation of CETP activity and plasma cholesterol to in normolipidemic the patients were Thus, the of the CETP of apoC1 in patients with lipoprotein might have a significant to the reduction in cholesteryl ester transfer rates It in to the in CETP and apoB-containing lipoprotein treatment M.J. M. Cholesteryl ester transfer protein: at the heart of the of with and cholesteryl ester transfer protein Heart J. 2010; PubMed Scopus Google Scholar). might for the or of CETP of apoC1 in subgroups of patients with hypercholesterolemia, hypertriglyceridemia, or combined all higher plasma levels with patients in the normolipidemic and in with earlier in patients R. A.M. 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Masson D. et of the of plasma cholesteryl ester transfer protein by inhibitor apolipoprotein Biol. Full Text Full Text PDF PubMed Scopus Google and VLDL-bound apoC1, apoC1, was found to be as a CETP inhibitor D. T. Pais de Barros J.P. P. L. Masson D. plasma apolipoprotein a for lipoprotein 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In of the blunted of apoC1 apoB-containing lipoproteins report that plasma positively with VLDL-bound apoC1 in a group of healthy subjects. It that the concomitant enrichment of lipoproteins with cholesterol and apoC1, which was to earlier in men with atherosclerosis S. R. de J. apolipoprotein content of lipoproteins independently atherosclerosis in healthy Am. Coll. Cardiol. PubMed Scopus Google Scholar) or CAD J. S. P. P. of apolipoprotein and in normolipidemic patients with coronary artery PubMed Scopus Google Scholar) could at in to plasma CETP activity, because apoC1 no longer operates as a CETP inhibitor to apoB-containing It might also for the recent that apoC1 is an risk and not a in patients with and de J.A. levels are associated with atherosclerosis in men with the and 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). that apoC1 has the to inhibit CETP activity in normolipidemic subjects, to the modulation of cholesterol between HDL and apoB-containing and in normolipidemic apoC1 not as a CETP inhibitor in patients, in particular those with or combined hyperlipidemia. in this treatment with pharmacological CETP inhibitors might compensate for blunted endogenous CETP inhibition is for with coronary artery disease cholesteryl ester transfer protein HDL-cholesterol LDL-cholesterol myocardial myocardial total cholesterol lipoprotein