Vaccine-Induced Antibodies Inhibit CETP Activity In Vivo and Reduce Aortic Lesions in a Rabbit Model of Atherosclerosis

Rittershaus, Charles W.; Miller, David P.; Thomas, Lawrence J.; Picard, Michele; Honan, Christopher M.; Emmett, Constance D.; Pettey, Carolyn L.; Adari, Hedy; Hammond, Russell A.; Beattie, David T.; Callow, Allan D.; Marsh, Henry C.; Ryan, Una S.

doi:10.1161/01.atv.20.9.2106

Cited by 288 publications

(158 citation statements)

References 52 publications

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“…52 Rabbits immunized with a peptide containing a region of the CETP molecule required for neutral lipid transfer function developed antibodies against CETP, with a significant reduction in plasma CETP activity and alterations in the lipoprotein profile. 53 The fraction of plasma cholesterol in HDL was 42% higher and the fraction of plasma cholesterol in LDL was 24% lower in the immunized group than in controls. The extent of aortic surface covered by atherosclerotic plaque was reduced by 39.6%.…”

Section: Is Cetp Inhibition Antiatherogenic?mentioning

confidence: 84%

“…25,26,32 Because reverse cholesterol transport is controlled at several discrete steps by different protein regulators and receptors, CETP inhibition is only one of several potential approaches for augmenting reverse cholesterol transport 49,59 -63 (see the Table). 49,53,54,58,62,[63][64][65][66][67] In fact, the clinical efficacy of pharmacological CETP inhibition could be substantially influenced by both diet and drugs that alter CETP pharmacokinetics. For instance, body weight influences CETP activity.…”

Section: Extension To Human Investigationmentioning

confidence: 99%

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Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

2005

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Abstract-Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol.Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by Ͼ50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ lipids Ⅲ metabolism Ⅲ statins A lthough lipid-lowering therapies now have the capability of reducing LDL cholesterol to levels recommended by the National Cholesterol Education Program (NCEP) guidelines in as many as 90% of treated patients, 1 the rate of cardiovascular events is reduced by only 20% to 35% in large, randomized trials. These data suggest that the LDL target set by NCEP guidelines may be too high. 1-5 Indeed, among patients with acute myocardial infarction, Ϸ15% have LDL levels Ͻ100 mg/dL on presentation.A complementary hypothesis is that there is a finite limit to the benefit of LDL lowering and that other non-LDL lipid risk factors must be managed for optimal outcomes. Indeed, epidemiological studies suggest that low HDL cholesterol may be a risk factor comparable in importance to high LDL and that the 2 risk factors are independent (Figure 1). 6,7 Although the mechanism by which HDL reduces the development of atherosclerosis has not been defined with certainty, acceleration of reverse cholesterol transport, antioxidant activity, and antiinflammatory action are likely to play central roles. 8 -10 In contrast to the ability of potent statins to reduce the level of LDL by Ͼ50%, however, no currently approved therapy increases HDL by a comparable magnitude. The most potent, currently available HDL-raising therapy is nicotinic acid. This therapy also has a multitude of other antiatherosclerotic effects on the levels of LDL and triglycerides, lipid oxidation, and endothelial function. 11 Combination therapy with a statin has been reported to increase HDL levels by Ϸ30% 12 and to decrease cardiac events...

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Section: Is Cetp Inhibition Antiatherogenic?mentioning

confidence: 84%

Section: Extension To Human Investigationmentioning

confidence: 99%

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

2005

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“…Studies in rabbits, which develop high CETP plasma levels on a high-cholesterol diet, 28 have shown that CETP inhibition by JTT-705 can protect against atherosclerosis. [11][12][13] Studies in mice, which are CETP deficient by nature, however, showed that expression of human CETP can be either atherogenic 29,30 or antiatherogenic. 31 To date, the precise role of CETP in human atherogenesis and how its activity relates to coronary artery disease risk is still unclear, 32,33 but JTT-705 is an effective tool to study these relations.…”

Section: Discussionmentioning

confidence: 99%

“…10 Also, antisense oligodeoxynucleotides against CETP mRNA, as well as a vaccine that elicits antibodies that block CETP function, lead to significant increases in HDL-C, accompanied by a marked reduction of aortic cholesterol content in rabbits. 11,12 Among others, these insights have led to the development of JTT-705, a compound that inhibits CETP activity by forming a disulphide bond with this protein. In cholesterolfed rabbits, JTT-705 increased plasma HDL-C, decreased non-HDL-C and, importantly, resulted in a 70% decrease of aortic arch lesions.…”

mentioning

confidence: 99%

Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans

et al. 2002

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Background-Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. Methods and Results-In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity (PϽ0.0001), a 34% increase in HDL cholesterol (PϽ0.0001), and a 7% decrease in LDL cholesterol (Pϭ0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL 2, HDL 3 , and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. Conclusions-We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects (Pϭ0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

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“…204,205 By contrast, in hypertriglyceridemic mouse models and in mice overexpressing LCAT, CETP overexpression reduced atherosclerosis despite lowering HDL-cholesterol. 204,205 In rabbits, vaccination against CETP 206 as well as CETP inhibition with either JTT705 (= dalcetrapib), 207 torcetrapib, 208 or antisense-nucleotides 209 were found to increase HDL-cholesterol and reduce atherosclerosis.…”

Section: Fibratesmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Vaccine-Induced Antibodies Inhibit CETP Activity In Vivo and Reduce Aortic Lesions in a Rabbit Model of Atherosclerosis

Cited by 288 publications

References 52 publications

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

Efficacy and Safety of a Novel Cholesteryl Ester Transfer Protein Inhibitor, JTT-705, in Humans

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

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