Cholesteryl Ester Transfer Protein Research Articles

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis' efficacy. We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible. major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality. stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI). Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81-0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86-0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes. Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

Cholesteryl ester transfer protein knock-down in conjunction with a cholesterol-depleting agent decreases tamoxifen resistance in breast cancer cells.

The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation and survival. Previously, the role of cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast cancer aggressiveness, but the molecular basis of this observation is not clearly understood, which this study aims to elucidate. CETP knock-down resulted in a >50% decrease in cell proliferation in both 'estrogen receptor-positive' (ER+; Michigan Cancer Foundation-7 (MCF7) breast cancer cells) and 'triple-negative' breast cancer (TNBC; MDA-MB-231) cell lines. Intriguingly, the abrogation of CETP together with the combination treatment of tamoxifen (5 μM) and acetyl plumbagin (a cholesterol-depleting agent) (5 μM) resulted in twofold to threefold increase in apoptosis in both cell lines. CETP knockdown also showed decreased intracellular CE levels, lipid raft and lipid droplets in both cell lines. In addition, RT2 Profiler PCR array (Qiagen, Germany)-based gene expression analysis revealed an overall downregulation of genes associated in cholesterol biosynthesis, lipid signalling and drug resistance in MCF7 cells post-CETP knock-down. On the contrary, resistance in MDA-MB-231 cells was reduced through increased expression in cholesterol efflux genes and the expression of targetable surface receptors by endocrine therapy. The pilot xenograft mice study substantiated CETP's role as a cancer survival gene as knock-down of CETP stunted the growth of TNBC tumour by 86%. The principal findings of this study potentiate CETP as a driver in breast cancer growth and aggressiveness and thus targeting CETP could limit drug resistance via the reduction in cholesterol accumulation in breast cancer cells, thereby reducing cancer aggressiveness.

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

Guiding Dyslipidemia Treatment: A Population Pharmacokinetic-Pharmacodynamic Framework for Obicetrapib.

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3-compartment model with 4-compartment transit absorption and first-order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations. The maximum stimulatory effect of obicetrapib on LDL-C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL-C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL-C and HDL-C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision-making throughout the development lifecycle.

Discovery of novel cholesteryl ester transfer protein (CETP) inhibitors by a multi-stage virtual screening

Cholesteryl ester transfer protein (CETP) is a promising therapeutic target for cardiovascular diseases. It effectively lowers the low-density lipoprotein cholesterol levels and increases the high-density lipoprotein cholesterol levels in the human plasma. This study identified novel and highly potent CETP inhibitors using virtual screening techniques. Molecular docking and molecular dynamics (MD) simulations revealed the binding patterns of these inhibitors, with the top 50 compounds selected according to their predicted binding affinity. Protein–ligand interaction analyses were performed, leading to the selection of 26 compounds for further evaluation. A CETP inhibition assay confirmed the inhibitory activities of the selected compounds. The results of the MD simulations revealed the structural stability of the protein–ligand complexes, with the binding site remaining significantly unchanged, indicating that the five compounds (AK-968/40709303, AG-690/11820117, AO-081/41378586, AK-968/12713193, and AN-465/14952302) identified have the potential as active CETP inhibitors and are promising leads for drug development.Graphical

Obicetrapib on top of maximally tolerated lipid‐modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN

Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a) and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.

Atherosclerosis Residual Lipid Risk-Overview of Existing and Future Pharmacotherapies.

Patients with atherosclerotic disease remain at increased risk of future events despite receiving optimal medical treatment. This residual risk is widely heterogeneous, but lipoprotein particles and their content play a major role in determining future cardiovascular events. Beyond low-density lipoprotein cholesterol (LDL-c), other lipoprotein particles have not demonstrated similar contribution to the progression of atherosclerosis. Statins, ezetimibe, and more recently, proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors and bempedoic acid have confirmed the causal role of LDL-c in the development of atherosclerosis. Data on high-density lipoprotein cholesterol (HDL-c) suggested a possible causal role for atherosclerosis; nonetheless, HDL-c-raising treatments, including cholesteryl-ester transfer protein (CETP) inhibitors and niacin, failed to confirm this relationship. On the other hand, mendelian randomisation revealed that triglycerides are more implicated in the development of atherosclerosis. Although the use of highly purified eicosapentaenoic acid (EPA) was associated with a reduction in the risk of adverse cardiovascular events, this beneficial effect did not correlate with the reduction in triglycerides level and has not been consistent across large phase 3 trials. Moreover, other triglyceride-lowering treatments, such as fibrates, were not associated with a reduction in future cardiovascular risk. Studies assessing agents targeting angiopoietin-like 3 (lipoprotein lipase inhibitor) and apolipoprotein C3 antisense will add further insights into the role of triglycerides in atherosclerosis. Emerging lipid markers such as lipoprotein (a) and cholesterol efflux capacity may have a direct role in the progression of atherosclerosis. Targeting these biomarkers may provide incremental benefits in reducing cardiovascular risk when added to optimal medical treatment. This Review aims to assess available therapies for current lipid biomarkers and provide mechanistic insight into their potential role in reducing future cardiovascular risk.

Multi analytical approach to find out the risk factors in terms of single nucleotide polymorphisms in patients with coronary artery disease in Indian Asian Population

Background 
 Researches have revealed a connection between CAD (coronary artery disease) and genetics, with various biochemical tests established to evaluate its severity. The incorporation of bioinformatics has advanced biomedical research and improved data management efficiency. The current study's objective was to identify risk factors in terms of Single Nucleotide Polymorphisms, associated with CAD in an Indian Asian population, utilizing a combined approach
 Methods
 The present study was completed in two phases: First phase was a literature search for susceptible SNPs and Second comprised of a cross sectional study. In first phase, using bioinformatic techniques like PubMed parser and Natural Language Processing (NLP) and manual search, we tried to find out susceptible polymorphisms to CAD. In second step, Global Screening Array (GSA) (Illumina) was performed in extracted DNA samples of 97cases and 36 controls. Different biochemical tests like Hemogram, Lipids, Fasting Blood Sugar (FBS), LFT, KFT, Vitamin D and HbA1C were also done as per standard protocol.
 Results
 In literature search from 134 studies conducted across several continents and various populations with more a million cases and controls, we could retrieve a comprehensive dataset of 261 susceptible SNPs with pooled Odd’s ratio of 1.196.
 On observing 261susceptible SNPs in our GSA results, we could find 5 SNPs with significant p value including rs187238 of IL-18 gene at chromosome 11, rs731236 and rs2228570 of VDR gene at chromosome 12, rs11556218 of gene IL16 at chromosome 15 and rs5882 of CETP gene at chromosome 16. The earlier studies had reported association of these with several disease conditions and for CAD, pathways related to endothelial damage, susceptibility of vitamin D receptor (VDR) polymorphisms and lowering HDL-cholesterol and ultimately causing CAD. But among Indian population, all only rs5882 has been studied in CAD cases and that too has not shown any association. The polymorphisms regarding VDR gene are also novel in Indian population, further biochemical co-relation done in both cases and controls revealed more percentage of Vitamin D deficient in healthy controls.
 Conclusion
 To conclude, a set of 261 susceptible SNPs for CAD was gathered and out of which association of 5 SNPs in the Indian Asian population was observed. Further, this pool can be validated in different ethnic groups and may provide a valuable screening tool to separate the vulnerable high-risk population where primary prevention strategies can be implemented. We could find, the Vitamin D deficiency may be key reason for developing the disease and further, an alarming condition for seemingly healthy population.

Synthesis and In-Silico Studies of Ortho-Fluorinated Benzenesulfonamides as Putative Anti-CETP Agents

Abstract: Cardiovascular disease is one of the primary causes of death. Atherosclerosis produces artery constriction or obstruction, which can lead to a heart attack or stroke. Cholesteryl Ester Transfer Protein (CETP) is a protein that aids in reverse cholesterol transport. It promotes cholesteryl ester transfer from HDL to LDL and VLDL. So, inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL cholesterol. In this study, ten ortho-fluoro substituted benzenesulfonamides 6a-6j were prepared, and their structure was fully determined using 1H NMR, 13C NMR, HR-MS, and IR. In vitro biological evaluation showed that compound 6d has the highest inhibitory activity with 100% inhibition, while compounds 6a-6c and 6e-6j had activities ranged from 29% - 83% at 10 μM concentration. Interestingly, para-substituted derivatives (6d, 6g, and 6j) were observed to have greater CETP inhibitory activities than their ortho- and meta- analogues irrespective to the nature of substituent, i.e., CH3, Cl, or NO2. Ligandfit docking experiment revealed the difference in the binding mode among the synthesized compounds, which is reflected in their CETP inhibitory activity. background: Cardiovascular disease is one of the primary causes of death. Atherosclerosis produces artery constriction or obstruction, which can lead to a heart attack or stroke. Cholesteryl ester transfer protein (CETP) is a protein that aids in reverse cholesterol transport. It promotes cholesteryl ester transfer from HDL to LDL and VLDL. So, inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL cholesterol. method: and their structure was fully determined using 1H-NMR, 13C-NMR, HR-MS, and IR. conclusion: Ligandfit docking experiment revealed the difference in the binding mode among the synthesized compounds which is reflected on their CETP inhibitory activity.

Uncovering the health implications of abandoned mines through protein profiling of local residents

Residents in areas with abandoned mines risk significant exposure to abundant heavy metals in the environment. However, current clinical indicators cannot fully reflect the health changes associated with abandoned mine exposure. The aim of this study was to identify biological changes in the residents of abandoned mine areas via proteomic analysis of their blood. Blood samples were collected from abandoned mine and control areas, and mass spectrometry was used for protein profiling. A total of 138 unique or common proteins that were differentially expressed in low-exposure abandoned mine area (LoAMA) or high-exposure abandoned mine area (HiAMA) compared to non-exposure control area (NEA) were analyzed, and identified 4 clusters based on functional similarity. Among the 10 proteins that showed specific change in LoAMA, 4 proteins(Apolipoprotein M, Apolipoprotein E, Apolipoprotein L1, and Cholesteryl ester transfer protein) were cluded in cluster 1(plasma lipoprotein remodeling), and linked to proteins that showed specific change in protein expression in HiAMA. Therefore, it is suggested that 4 proteins are changed at low exposure to an abandoned mine (or initial exposure), and then at high exposure, changes in various proteins involved in linked plasma lipoprotein remodeling are induced, which might triggered by the 4 proteins. Interestingly, in addition to plasma lipoprotein remodeling, proteins involved in other functional networks were changed in the high exposure group. These were all directly or indirectly linked to the 4 biomarkers(Apolipoprotein M, Apolipoprotein E, Apolipoprotein L1, and Cholesteryl ester transfer protein) that changed during low exposure. This suggests their potential utility in identifying areas impacted by abandoned mines. Especially, proteins involved in lipid metabolism and renal function-related diseases in individuals exposed to heavy metals in abandoned mine areas were correlated. Chronic kidney disease is predominantly instigated by cardiovascular disease and is commonly accompanied by dyslipidemia.

Cholesterol Ester Transfer Protein Taq1B Polymorphism and Its Association with Cardiovascular Risk Factors in Patients Undergoing Angiography in Yazd, Eastern Iran: A Cross-Sectional Study.

Several studies assessed the relationship between the cholesterol ester transfer protein (CETP) Taq1B gene polymorphism (rs708272) with risk factors of cardiovascular diseases (CVDs). However, their findings were inconsistent. The present study investigated the relationship between CVD risk factors and the Taq1B variant in patients undergoing coronary angiography. This cross-sectional study was conducted on 476 patients aged 30-76 years old of both sexes from 2020-2021, in Yazd (Iran). The Taq1B polymorphism genotypes were evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on DNA extracted from whole blood. Standard protocols were used to measure cardio-metabolic markers. To determine the association between CVDs risk factors and the rs708272 variant, binary logistic regression was used in crude and adjusted models. Taq1B polymorphism genotype frequencies were 10.7% for B1B1, 72.3% for B1B2, and 17% for B2B2. There was no significant association between abnormal levels of CVDs risk factors and different genotypes of the Taq1B variant, Gensini score (P=0.64), Syntax score (P=0.79), systolic blood pressure (P=0.55), diastolic blood pressure (P=0.58), and waist circumference (P=0.79). There was no significant association between genotypes of the rs708272 variant and any abnormal serum lipid levels. After adjusting for confounders, the results remained non-significant. There was no significant association between CVDs risk factors and CETP rs708272 polymorphism. The relationship between CETP gene variants and CVD occurrences varied across groups, implying that more research in different regions is required.A preprint version of this manuscript is available at https://www.researchsquare.com/article/rs-2575215/v1 with doi: 10.21203/rs.3.rs-2575215/v1.

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study

BackgroundObstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. MethodsA drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. ResultsGenetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60–0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93–1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. ConclusionsThe present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.

Carbohydrazide-Based schiff bases for selective Hg (II) ion sensing and computational analysis of cholesterol lowering activity

The presence of mercury ion (Hg (II)) in the environment is a serious health concern. Therefore, it is essential to measure and monitor the levels of Hg (II) in the environment to safeguard public health. This study focuses on the synthesis of carbohydrazide-based Schiff bases (4–5) and exhibit a red-shift in absorption upon addition of Hg (II) ion, making them highly selective and sensitive in detecting Hg (II). The confirmation of the synthesized compounds was achieved using (1H and 13C) NMR spectroscopy and mass spectrometry. Additionally, the detection limits towards Hg (II) were determined to be 7.56 × 10-7 M and 1.42 × 10-6 M for compounds 4 and 5, respectively. The 1H NMR spectra provided evidence of interactions between compounds 4–5 and Hg (II) ion. The compounds 4 and 5 were evaluated for Bioactivity, Drug likeness parameters and Prediction of Activity Spectra (PASS) analysis to design a new molecule with a favorable pharmacological profile. Based on the PASS results, molecular docking studies of compounds 4 and 5 were performed with Cholesteryl Ester Transfer Protein (CETP) (PDB ID: 2OBD), revealing inhibitory activity. These findings suggest the potential of these compounds as candidates for antihyperlipidemic or cholesterol-lowering agents.

Zebrafish ApoB-Containing Lipoprotein Metabolism: A Closer Look.

Zebrafish have become a powerful model of mammalian lipoprotein metabolism and lipid cell biology. Most key proteins involved in lipid metabolism, including cholesteryl ester transfer protein, are conserved in zebrafish. Consequently, zebrafish exhibit a human-like lipoprotein profile. Zebrafish with mutations in genes linked to human metabolic diseases often mimic the human phenotype. Zebrafish larvae develop rapidly and externally around the maternally deposited yolk. Recent work revealed that any disturbance of lipoprotein formation leads to the accumulation of cytoplasmic lipid droplets and an opaque yolk, providing a visible phenotype to investigate disturbances of the lipoprotein pathway, already leading to discoveries in MTTP (microsomal triglyceride transfer protein) and ApoB (apolipoprotein B). By 5 days of development, the digestive system is functional, making it possible to study fluorescently labeled lipid uptake in the transparent larvae. These and other approaches enabled the first in vivo description of the STAB (stabilin) receptors, showing lipoprotein uptake in endothelial cells. Various zebrafish models have been developed to mimic human diseases by mutating genes known to influence lipoproteins (eg, ldlra, apoC2). This review aims to discuss the most recent research in the zebrafish ApoB-containing lipoprotein and lipid metabolism field. We also summarize new insights into lipid processing within the yolk cell and how changes in lipid flux alter yolk opacity. This curious new finding, coupled with the development of several techniques, can be deployed to identify new players in lipoprotein research directly relevant to human disease.

Novel Therapeutic Approaches for the Management of Elevated Lipoprotein(a): From Traditional Agents to Future Treatment Options.

Cardiovascular disease is the leading cause of mortality worldwide. Despite the availability of effective low-density lipoprotein cholesterol (LDL-C) lowering agents, an increased cardiovascular risk is still observed in individuals with therapeutic LDL-C levels. One of these cardiovascular risk factors is elevated plasma lipoprotein(a) (Lp(a)) concentration, which maintains chronic inflammation through the increased presence of oxidized phospholipids on its surface. In addition, due to its 90 percent homology with the fibrinolytic proenzyme plasminogen, Lp(a) exhibits atherothrombotic effects. These may also contribute to the increased cardiovascular risk in individuals with high Lp(a) levels that previous epidemiological studies have shown to exist independently of LDL-C and other lipid parameters. In this review, the authors overview the novel therapeutic options to achieve effective Lp(a) lowering treatment, which may help to define tailored personalized medicine and reduce the residual cardiovascular risk in high-risk patients. Agents that increase LDL receptor expression, including statins, proprotein convertase subtilisin kexin type 9 inhibitors, and LDL production inhibitors, are also discussed. Other treatment options, e.g., cholesterolester transfer protein inhibitors, nicotinic acid derivatives, thyroid hormone mimetics, lipoprotein apheresis, as well as apolipoprotein(a) reducing antisense oligonucleotides and small interfering RNAs, are also evaluated.

Beyond Statins: Novel Lipid-Lowering Agents for Reducing Risk of Atherosclerotic Cardiovascular Disease

Although statins have served as the cornerstone for pharmacological lowering of lipid levels in atherosclerotic cardiovascular disease (ASCVD) risk reduction, many patients are unable to achieve target doses of statin medication due to side effects or target levels of cholesterol reduction on statin monotherapy. The landscape of lipid-lowering strategies has expanded in recent years, with the emergence of therapies that make use of small interfering RNA (siRNA) and antisense oligonucleotides, in addition to traditional small-molecule agents. Non-statin therapies that have shown promising results in randomized controlled trials include adenosine triphosphate-citrate lyase inhibitors, proprotein convertase subtilisin/kexin 9 (PCSK9)-inhibiting antibodies and siRNA, omega-3 polyunsaturated fatty acids, and lipoprotein(a) gene-inhibiting siRNA and ASOs, in addition to older therapies such as ezetimibe. In contrast, cholesteryl ester transfer protein (CETP) inhibitors have shown less promising results in randomized trials. The purpose of this narrative review is to summarize the evidence for these medications, with a focus on phase III randomized trials.

Cholesteryl Ester Transfer Protein (CETP) Variations in Relation to Lipid Profiles and Cardiovascular Diseases: An Update.

Lipid metabolism plays an essential role in the pathogenesis of cardiovascular and metabolic diseases. Cholesteryl ester transfer protein (CETP) is a crucial glycoprotein involved in lipid metabolism by transferring cholesteryl esters (CE) and triglycerides (TG) between plasma lipoproteins. CETP activity results in reduced HDL-C and increased VLDL- and LDL-C concentrations, thus increasing the risk of cardiovascular and metabolic diseases. In this review, we discuss the structure of CETP and its mechanism of action. Furthermore, we focus on recent experiments on animal CETP-expressing models, deciphering the regulation and functions of CETP in various genetic backgrounds and interaction with different external factors. Finally, we discuss recent publications revealing the association of CETP single nucleotide polymorphisms (SNPs) with the risk of cardiovascular and metabolic diseases, lifestyle factors, diet and therapeutic interventions. While CETP SNPs can be used as effective diagnostic markers, diet, lifestyle, gender and ethnic specificity should also be considered for effective treatment.

Atherosclerosis: an overview of mouse models and a detailed methodology to quantify lesions in the aortic root.

Cardiovascular disease, the primary cause of human mortality globally, is predominantly caused by a progressive disorder known as atherosclerosis. Atherosclerosis refers to the process of accumulation of cholesterol-enriched lipoproteins and the concomitant initiation of inflammatory processes in the arterial wall, including the recruitment of immune cells. This leads to the formation of atherosclerotic plaques, initially causing a thickening of the arterial wall and narrowing of arteries. However, as plaque formation progresses, atherosclerotic plaques may become unstable and rupture, leading to a blood clot that blocks the affected artery or travels through the blood to block blood flow elsewhere. In the early 1990s, emerging gene editing methods enabled the development of apolipoprotein E knockout (Apoe-/- ) and low-density lipoprotein receptor knockout (Ldlr-/- ) mice. These mice have been instrumental in unraveling the complex pathogenesis of atherosclerosis. Around the same time, human APOE*3-Leiden transgenic mice were generated, which were more recently cross-bred with human cholesteryl ester transfer protein (CETP) transgenic mice to generate APOE*3-Leiden.CETP mice. This model appears to closely mimic human lipoprotein metabolism and responds to classic lipid-lowering interventions due to an intact ApoE-LDLR pathway of lipoprotein remnant clearance. In this review, we describe the role of lipid metabolism and inflammation in atherosclerosis development and highlight the characteristics of the frequently used animal models to study atherosclerosis, with a focus on mouse models, discussing their advantages and limitations. Moreover, we present a detailed methodology to quantify atherosclerotic lesion area within the aortic root region of the murine heart, as well as details required for scoring atherosclerotic lesion severity based on guidelines of the American Heart Association adapted for mice.

Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein.

Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL. This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis. Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 μM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness. It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.