Pathophysiology and inhibition of cholesteryl ester transfer protein for prevention of cardiovascular diseases: An update

Banerjee, Surojit; De, Abhijit

doi:10.1016/j.drudis.2021.03.016

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…It is well known that CETP is a key enzyme involved in cholesterol metabolism and transportation, which transfers cholesteryl esters from HDL to low-density lipoprotein (LDL) in exchange for triglycerides. In the past decades, CETP has been considered to be one of the most ideal targets for lipid-lowering, and inhibition of CETP could improve cardiovascular disease outcomes [27,28]. Earlier research studies have shown that multiple CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, and anacetrapib, were designed to raise plasma HDL-C levels; however, most of these compounds except for anacetrapib failed to reduce the risk for cardiovascular disease due to compound-specific reasons [29].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Cholesteryl Ester Transfer Protein Contributes to the Protection of Ginsenoside Re Against Isoproterenol-Induced Cardiac Hypertrophy

Qiu,

Xie,

Ding

et al. 2024

Cureus

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Background and objectivesGinsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the mechanisms of Re in improving cardiac hypertrophy have not been fully elucidated. This study aimed to investigate the therapeutic effects and underlying mechanism of Re on isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro. MethodsRats were intraperitoneally injected with ISO 30 mg/kg thrice daily for 14 consecutive days to induce cardiac hypertrophy, and these rats were treated with atorvastatin (ATC, 20 mg/kg) or Re (20 mg/kg or 40 mg/kg) once daily for three days in advance until the end of the experiment. Heart weight index, hematoxylin and eosin staining, and hypertrophy-related fetal gene expression were measured to evaluate the effect of Re on cardiac hypertrophy in vivo. Meanwhile, the rat H9c2 cardiomyocyte hypertrophy model was induced by ISO 10 μM for 24 hours. Cell surface area and hypertrophy-related fetal gene expression were determined to assess the effect of Re on ISO-induced cardiomyocyte hypertrophy in vitro. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in both serum and cardiomyocytes were detected by enzymatic colorimetric assays. Furthermore, we chose cholesteryl ester transfer protein (CETP) as a target to explore the influence of Re on CETP expression in vivo and in vitro through real-time polymerase chain reaction, western blot, and enzymelinked immunosorbent assay. ResultsIntraperitoneal administration of ISO into rats resulted in increases in cross-sectional cardiomyocyte area, the ratio of heart weight to body weight, the ratio of left ventricular weight to body weight, and the ratio of right ventricular weight to body weight, as well as reactivation of fetal genes; however, treatment with Re or ATC ameliorated most of these hypertrophic responses. Similarly, Re pronouncedly alleviated ISO-induced cardiomyocyte hypertrophy, as evidenced by a decreased cell surface area and downregulation of fetal genes. Moreover, our in vivo and in vitro data revealed that Re reduced TC, TG, and LDL-C levels, and enhanced HDL-C levels. Re improved cardiac hypertrophy mainly associated with the inhibition of mRNA level and protein expression of CETP, to an extent comparable to that of the classical CETP inhibitor, anacetrapib. ConclusionsOur research found that CETP inhibition contributes to the protection of Re against ISO-induced cardiac hypertrophy, which provides evidence for the application of Re for cardiovascular disease treatments.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Cholesteryl Ester Transfer Protein Contributes to the Protection of Ginsenoside Re Against Isoproterenol-Induced Cardiac Hypertrophy

Qiu,

Xie,

Ding

et al. 2024

Cureus

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“…Obicetrapib, which is well tolerated, has beneficial effects on lipids and apolipoproteins, without any serious adverse effect observed in other CETP inhibitor trials [ 129 ]. As reported, obicetrapib, as a monotherapy or concurrently with a statin to improve the concentrations of HDL-C and LDL-C is a promising drug for treating ASCVD outcomes [ 127 , 129 , 130 ].…”

Section: Cetp Inhibitionmentioning

confidence: 99%

Structure-based mechanism and inhibition of cholesteryl ester transfer protein

Han

Zhang

Liu

et al. 2023

Curr Atheroscler Rep

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Purpose of Review Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition. Recent Findings Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Summary Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

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“…Additional research on this pathway is necessary. Furthermore, CETP inhibitors are able to fulfill a different role, which is protection against the development of diabetes mellitus, by increasing insulin responsiveness and boosting glucose tolerance [109][110][111].…”

Section: Cholesteryl Ester Transfer Protein (Cetp) Inhibitorsmentioning

confidence: 99%

Advances in Treatment of Dyslipidemia

Dybiec,

Baran,

Dąbek

et al. 2023

IJMS

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Dyslipidemias have emerged as prevalent disorders among patients, posing significant risks for the development and progression of cardiovascular diseases. These conditions are characterized by elevated levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C). This review delves into the current treatment approach, focusing on equalizing these parameters while enhancing the overall quality of life for patients. Through an extensive analysis of clinical trials, we identify disorders that necessitate alternative treatment strategies, notably familial hypercholesterolemia. The primary objective of this review is to consolidate existing information concerning drugs with the potential to revolutionize dyslipidemia management significantly. Among these promising pharmaceuticals, we highlight alirocumab, bempedoic acid, antisense oligonucleotides, angiopoietin-like protein inhibitors, apolipoprotein C-III (APOC3) inhibitors, lomitapide, and cholesterol ester transfer protein (CETP) inhibitors. Our review demonstrates the pivotal roles played by each of these drugs in targeting specific parameters of lipid metabolism. We outline the future landscape of dyslipidemia treatment, envisaging a more tailored and effective therapeutic approach to address this widespread medical concern.

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Pathophysiology and inhibition of cholesteryl ester transfer protein for prevention of cardiovascular diseases: An update

Cited by 13 publications

References 27 publications

Inhibition of Cholesteryl Ester Transfer Protein Contributes to the Protection of Ginsenoside Re Against Isoproterenol-Induced Cardiac Hypertrophy

Inhibition of Cholesteryl Ester Transfer Protein Contributes to the Protection of Ginsenoside Re Against Isoproterenol-Induced Cardiac Hypertrophy

Structure-based mechanism and inhibition of cholesteryl ester transfer protein

Advances in Treatment of Dyslipidemia

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