Development of new antiatherosclerotic agents--ACAT inhibitors and CETP inhibitors

Development of new antiatherosclerotic agents were reviewed focusing on ACAT inhibitors and CETP inhibitors. ACAT inhibitors enhance intracellular degradation of VLDL in hepatocytes. Cholesterol absorption in small intestine is inhibited by ACAT inhibitors. Thus, ACAT inhibitors reduce plasma cholesterol levels. In atherosclerotic lesions, ACAT inhibitors suppress foam cell formation (cholesteryl ester accumulation) in macrophages. Since ACAT inhibitors have multiple anti-atherogenic effects, they are considered future drugs controlling hypercholesterolemia and atherosclerosis. CETP inhibitors are expected to increase HDL and decrease LDL. Although the patients with CETP deficiency show high level of HDL, recent studies showed that they are not necessarily resistant to atherosclerosis. The strategy to inhibit CETP for suppressing atherosclerosis has not been established.     

Potential therapeutics for obesity and atherosclerosis: inhibitors of neutral lipid metabolism from microorganisms

Diacylglycerol acyltransferase (DGAT) and acyl-CoA: cholesterol acyltransferase (ACAT) are the enzymes that catalyze the final reactions of triacylgycerol (TG) and cholesteryl ester (CE) synthesis, and accumulation of TG and CE in adipocytes and arteries causes obesity and atherosclerosis, respectively. Therefore, DGAT and ACAT have been viewed as potential therapeutic targets for these diseases. From the screening program for DGAT inhibitors, new compounds were discovered from fungal and plant extracts, and are expected to provide leads for drug development. From the screening programs for ACAT inhibitors and lipid droplet synthesis inhibitors, new compounds with chemical structures different from those of known synthetic inhibitors were discovered from the cultures of fungal and actinomycete strains. Among them, fungal beauveriolide III rather selectively inhibited ACAT1 isozyme, while fungal pyripyropene A was found to be a highly selective inhibitor of ACAT2 isozyme. Both inhibitors proved orally active in in vivo models. Furthermore, a library of beauveriolide and pyripyropene analogs was prepared by combinatorial and semisynthetic methods, respectively. The future prospects of these inhibitors are discussed.     

Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1

Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted considerable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACATs. One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation. In this study, we examined the effects of selective ACAT1 deficiency in two mouse models of atherosclerosis. In the setting of severe hypercholesterolemia caused by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposition of unesterified cholesterol in the skin and brain. Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels. However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions. Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences.     

Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages

During atherogenesis, circulating macrophages migrate into the subendothelial space, internalize cholesterol-rich lipoproteins, and become foam cells by progressively accumulating cholesterol esters. The inhibition of macrophage acyl coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the formation of cholesterol esters, has been proposed as a strategy to reduce foam cell formation and to treat atherosclerosis. We show here, however, that hypercholesterolemic LDL receptor-deficient (LDLR(-/-)) mice reconstituted with ACAT1-deficient macrophages unexpectedly develop larger atherosclerotic lesions than control LDLR(-/-) mice. The ACAT1-deficient lesions have reduced macrophage immunostaining and more free cholesterol than control lesions. Our findings suggest that selective inhibition of ACAT1 in lesion macrophages in the setting of hyperlipidemia can lead to the accumulation of free cholesterol in the artery wall, and that this promotes, rather than inhibits, lesion development.     

Pharmacological characterization of diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), an intestine-specific inhibitor of microsomal triglyceride transfer protein

Inhibitors of microsomal triglyceride transfer protein (MTP) expressed in the liver and small intestine are potential candidates for lipid-lowering agents. However, inhibition of hepatic MTP could lead to significant safety issues such as fatty liver disease. To develop a specific inhibitor of intestinal MTP, JTT-130 [diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate], was designed to be rapidly hydrolyzed in the absorption process. Here, we describe JTT-130, an intestine-specific MTP inhibitor, and evaluate its pharmacological properties. In in vitro metabolic stability tests, JTT-130 was readily hydrolyzed during incubation with liver S9 from humans, hamsters, and rats. In an in vitro triglyceride (TG) transfer assay with human intestinal MTP, JTT-130 potently inhibited TG transfer activity with an IC(50) value of 0.83 nM. When orally administered to hamsters, JTT-130 significantly suppressed an increase in chylomicron-TG after olive oil loading at 0.3 mg/kg and above but did not inhibit TG secretion from the liver at doses of up to 1000 mg/kg, indicating an inhibitory action highly specific for the small intestine. In rats orally administered [(14)C]triolein, JTT-130 potently suppressed an increase in blood (14)C radioactivity and increased (14)C radioactivity in the upper small intestine and the intestinal lumen. In hyperlipidemic hamsters fed a high-fat and high-cholesterol diet, repeated dosing with JTT-130 for 2 weeks reduced TG and cholesterol levels in the plasma and TG content in the liver. These results indicated that JTT-130 is a potent inhibitor specific to intestinal MTP and suggested that JTT-130 would be a useful compound for the treatment of dyslipidemia without inducing hepatotoxicity.     

A small-molecule inhibitor of enterocytic microsomal triglyceride transfer protein, SLx-4090: biochemical, pharmacodynamic, pharmacokinetic, and safety profile

First-generation microsomal triglyceride transfer protein (MTP) inhibitors were designed to inhibit hepatic MTP and provide a novel treatment of dyslipidemia. Effective at lowering low-density lipoprotein-cholesterol (LDL-C), these inhibitors also elevate liver enzymes and induce hepatic steatosis in animals and humans. MTP is highly expressed in the enterocytes, lining the lumen of the jejunum, and is critical in the production of chylomicrons assembled from lipid/cholesterol and their transfer into systemic circulation. 6-(4'-Trifluoromethyl-6-methoxy-biphenyl-2-ylcarboxamido)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid phenyl ester (SLx-4090) (IC(50) value ～8 nM) was designed to inhibit only MTP localized to enterocytes. In Caco-2 cells SLx-4090 inhibited apolipoprotein B (IC(50) value ～9.6 nM) but not apolipoprotein A1 secretion. Administered orally to rats SLx-4090 reduced postprandial lipids by >50% with an ED(50) value ～7 mg/kg. SLx-4090 was not detected in the systemic or portal vein serum of the animals (lower limit of quantitation ～5 ng/ml) after single or multiple oral doses in fasted rodents. When coadministered with tyloxapol, SLx-4090 did not inhibit the secretion of hepatic triglycerides (TG), consistent with the absence of systemic exposure. Chronic treatment with SLx-4090 in mice maintained on a high-fat diet decreased LDL-C and TG and resulted in weight loss without the elevation of liver enzymes or an increase in hepatic fat. The compound did not result in toxicity when administered to rats for 90 days at a dose of 1000 mg/kg per day. These data support the concept that the inhibition of enterocytic MTP could serve as a useful strategy in the treatment of metabolic disorders.     

Lipoproteins and apolipoproteins in young nonobese Arab women with NIDDM treated with insulin

The effects of insulin on the lipid values of nonobese non-insulin-dependent diabetic (NIDDM) Arab women requiring insulin was investigated to find whether these patients have the same coronary artery risk factor related to lipid levels. In this study, 55 NIDDM women on insulin therapy (mean age 28 +/- 8.1 yr and duration of disease 5 +/- 1.2 yr) and 70 control subjects (matched for sex, age, and body mass index) were studied for their plasma levels of lipids, lipoproteins, and apolipoproteins. Concentrations of total cholesterol, very-low-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride (TG), LDL TG, high-density lipoprotein triglyceride (HDL TG), phospholipid, glucose, glycosylated hemoglobin (HbAtc), apolipoprotein B (apoB), LDL-apoB, and apoB/apoAl were significantly elevated in diabetic women compared with control subjects. There was no significant change in the levels of apoAll in plasma and lipoprotein fractions. Concentrations of HDL cholesterol (chol), HDL2-chol, HDL3-chol, plasma apoAl, HDL2-apoAl, HDL3-apoAl, and HDL-apoAl were significantly lower in diabetic women than in control subjects. There was no significant correlation between glucose or HbAtc and most of the lipids, lipoprotein lipids, and apolipoproteins measured. Despite normal body weight and insulin therapy, abnormalities in lipids, lipoprotein lipids, and apoB persisted in NIDDM patients compared with control subjects. Our data may favor an enhanced affinity toward atherosclerosis in these patients.     

What future for combination therapies?

For most patients who require lipid-lowering treatment, statin monotherapy is the appropriate treatment. However, in those patients where statin monotherapy does not produce optimal lipid levels, the combination of a statin with niacin, a bile acid sequestrant, a fibric acid derivative, a cholesterol absorption inhibitor or a fish oil preparation may provide improved control. The choice of combination therapy depends upon the patient's lipid profile and tolerability of the medication. Combination of a statin with niacin, a bile acid sequestrant or ezetimibe, a cholesterol absorption inhibitor, should be considered for patients with very high low-density lipoprotein cholesterol (LDL-C) levels, while combination with either a fibric acid derivative or a fish oil should be considered for patients with high LDL-C and high triglyceride levels. A number of new lipid-lowering agents are currently in development, including cholesteryl ester transfer protein (CETP) inhibitors, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, ileal bile acid transport (IBAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors and dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonists. Introduction of these novel therapies will provide opportunities for developing different combination strategies that may help to optimise lipid profiles in patients who are currently difficult to treat. The introduction of new combinations will require careful study to ensure that the risks of drug interactions and adverse events are minimised.     

New antilipemics: prospects

The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.     

纳豆激酶对动脉粥样硬化模型大鼠血脂及血液流变学影响

目的 研究纳豆激酶对动脉粥样硬化模型大鼠血脂及血液流变学的影响.方法 选取健康Wistar大鼠50只,随机均分为5组：正常对照组、动脉粥样硬化模型组、辛伐他汀组、低剂量NK组、高剂量NK组.高脂饲料复制动脉粥样硬化大鼠模型,药物组每天灌胃给药1次,连续4周.正常组和模型组每天等体积蒸馏水灌胃,辛伐他汀组按4 mg/kg体重,纳豆激酶低、高组（56 FU、280 FU/kg体重）,每天灌胃给药1次,自由进食与进水,连续4周.5组动物分别测定：总胆固醇（ TC）、甘油三酯（ TG）、低密度脂蛋白（ LDL-C）、高密度脂蛋白胆固醇（HDL-C）、全血低切、中切及高切黏度,血浆黏度,血浆纤维蛋白原浓度（Fib）;红细胞压积（Hct）;红细胞电泳时间（RCET）;测血沉（ESR）.结果 纳豆激酶可显著降低动脉硬化模型大鼠血脂水平,使全血黏度、血浆黏度、红细胞压积、血沉、红细胞电泳时间、血浆纤维蛋白原浓度都显著降低.结论 纳豆激酶可改善动脉粥样硬化模型大鼠血脂水平和血液流变学,对动脉粥样硬化具有防治作用.     

超敏C-反应蛋白在2型糖尿病并发动脉粥样硬化中的研究

目的 探讨血清超敏C-反应蛋白(Hs-CRP)、胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白-胆固醇(LDL-C)与2型糖尿病并发动脉粥样硬化的关系.方法 150例糖尿病患者(实验组)及50例健康对照者(对照组)均采用免疫比浊法测定Hs-CRP,氧化酶法测定TG、TC、一步法测定LDL-C水平,并进行相关性分析.结果 实验组Hs-CRP、TG、TC、LDL-C较对照组明显升高(P<0.001),血糖控制不良组(C组)中Hs-CRP明显高于血糖控制良好组(A组)和血糖控制一般组(B组)(P<0.01),B组高于A组(P<0.01)且与TG、TC、LDL-C正相关.结论 Hs-CRP、TG、TC、LDL-C与2型糖尿病并发动脉粥样硬化密切相关,可作为风险预测指标预测2型糖尿病并发症出现.     

冠状动脉粥样硬化性心脏病患者血浆脂联素水平及其与血脂、细胞黏附分子的相关性分析

目的 探讨冠状动脉粥样硬化性心脏病（冠心病,CHD）患者血浆脂联素水平变化及其与血脂、细胞黏附分子的关系。方法 酶联免疫吸附法（ELISA）测定30例冠心病患者（CHD组）和30例健康对照者（对照组）的血浆脂联素、血管细胞黏附分子1（VCAM1）、细胞间黏附分子1（ICAM1）及E-选择素水平;酶法测定血浆总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）水平。结果 CHD组与对照组相比,TG、TC和LDL水平明显增高（P〈0．001）,HDL明显降低（P〈0．001）;血浆脂联素水平显著降低（P〈0．001）,血浆VCAM1、ICAM1和E-选择素水平显著升高（P〈0．001）;血浆脂联素水平与TC、TG、LDL水平呈负相关（P〈0．001）,与HDL成正相关（P〈0．001）,与血浆VCAM1、ICAM1、E-选择素水平成负相关。结论 血浆脂联素水平异常与冠心病的发生密切相关。     

Effect of the ACAT inhibitor CI-976 on plasma cholesterol concentrations and distribution in hamsters fed zero- and low-cholesterol diets.

The overall objective of the present study was to determine if the ACAT inhibitor CI-976 can lower plasma cholesterol in hamsters fed zero or low, "human-like" levels of cholesterol. With a purified diet containing zero dietary cholesterol, CI-976 significantly lowered VLDL cholesterol (VLDL-C), but not total plasma cholesterol (TPC). When 0.06% cholesterol was added to this diet, reductions in both VLDL and LDL cholesterol (LDL-C) lowered TPC. Efficacy was still greater with 0.2% dietary cholesterol, but not potency. Mixing CI-976 into the purified diet resulted in greater decreases in VLDL-C compared to gavage administration, but LDL-C reductions with 0.2% cholesterol were optimal with gavage. With nonpurified, chow-based diets efficacy was markedly greater with diet-admix administration, regardless of the amount of dietary cholesterol. CI-976 inhibited cholesterol absorption with chow-based diets more potently compared to nonabsorbable agents (e.g., beta-sitosterol, tigogenin cellobioside), and the lowering of LDL-C was greatest when inhibition of cholesterol absorption was maximal. We conclude that the ACAT inhibitor CI-976 is efficacious in hamster models which utilize human-like levels of dietary cholesterol. Moreover, the data suggest that the pharmacologic responses to lipophilic ACAT inhibitors in the hamster, or even other lipid-regulating drugs, are likely to depend not only on the type of basal diet but also on the mode of drug administration.     

Acyl coenzyme A: cholesterol acyltransferase inhibition and hepatic apolipoprotein B secretion.

Acyl coenzyme A: cholesterol acyltransferase (ACAT) is postulated to play a role in hepatic and intestinal lipoprotein secretion. There is accumulating evidence, both in vitro and in vivo, that cholesterol and/or cholesteryl ester availability can regulate hepatic VLDL secretion. How ACAT inhibition regulates the assembly and secretion of apolipoprotein (apo) B containing lipoproteins within the hepatocyte has not been clearly established. ApoB kinetic studies performed in animals indicate that reduction in VLDL apoB secretion is an important mechanism whereby ACAT inhibitors decrease the plasma concentrations of these lipoproteins. However, in cultured hepatocytes, the effect of ACAT inhibition on apoB secretion has been inconsistent. Recent evidence has suggested the existence of more than one ACAT enzyme in mammals, which has culminated in the recent cloning of ACAT2. ACAT1 and ACAT2 respond differently to ACAT inhibitors of differing structures and classes. ACAT2 is present in the liver and intestine, the sites of apoB containing lipoprotein secretion and may represent the enzyme responsible for generating cholesteryl esters destined for lipoprotein assembly and secretion.     

Microsomal triglyceride transfer protein polymorphisms and lipoprotein levels in type 2 diabetes

BACKGROUND: Microsomal triglyceride transfer protein (MTP) regulates the assembly of chylomicrons in the intestine and very-low-density lipoprotein (VLDL) in the liver. Common polymorphisms have been described that do not affect lipoproteins in non-diabetic subjects. Their effect in diabetes has not been described in a Caucasian population. AIM: To investigate the association of these three common polymorphisms with lipoproteins in type 2 diabetes. METHODS: Eighty-two patients consumed a high-fat test meal. Chylomicron and VLDL apoB48, apoB100, cholesterol, triglycerides and phospholipids were measured fasting, and at 4 and 6 h postprandially. MTP genotyping was performed by PCR-RFLP. RESULTS: Thirty-three subjects were heterozygous for the -493 G/T substitution. These patients had significantly lower LDL cholesterol (3.0 +/- 0.2 vs. 3.5 +/- 0.1 mmol/l, p < 0.02). In the postprandial period, they had higher levels of apoB48 in the VLDL fraction (4 h, 7.0 +/- 1.4 vs. 2.9 +/- 0.4 microg/ml plasma, p < 0.002; 6 h, 6.4 +/- 1.0 vs. 3.5 +/- 0.5 microg/ml plasma, p < 0.05). In the VLDL fraction there was significantly less cholesterol at 4 and 6 h (p < 0.05). The -400 A/T substitution gave very similar lipoprotein results, but there was significant linkage dysequilibrium between the two polymorphisms. No association was found between the -164 T/C polymorphism and either plasma lipids or the postprandial lipid profile. ApoE genotype was also examined, but did not influence the above results. DISCUSSION: The common -493 G/T MTP polymorphism is associated with changes in VLDL and LDL in Type 2 diabetic patients. The importance of the changes in apoB48-containing small particles requires further investigation. The significantly lower LDL cholesterol suggests that this polymorphism may confer protection against atherosclerosis in type 2 diabetes.     

Fibrates

Fibrates regulates not only plasma lipid metabolism but vascular biology by activating nuclear receptor peroxisome proliferating activated alpha (PPAR alpha). Major effects on plasma lipid levels are lowering plasma triglyceride level and elevating plasma HDL cholesterol level, whereas its effect on plasma cholesterol level is moderate compared to HMG-CoA reductase inhibitor. As a mechanism for its effects on plasma lipid levels and atherosclerosis, recent studies reported that fibrates activates various genes involved in metabolism of remnants and HDL such as lipoprotein lipase, apo AI, apo AII, and apo CIII genes through the interaction with PPAR alpha, lowering atherogenic lipoproteins and elevating anti-atherogenic lipoproteins. Furthermore, fibrates may influence the process of atherosclerosis by modifying inflammatory process in vascular wall. Recent clinical studies demonstrated that fibrates significantly reduce cardiovascular events in patients with either hypertriglyceridemia or low HDL cholesterol level.     

Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice

Recent genome-wide association studies have identified a genetic locus at human chromosome 8q24 as having minor alleles associated with lower levels of plasma triglyceride (TG) and LDL cholesterol (LDL-C), higher levels of HDL-C, as well as decreased risk for myocardial infarction. This locus contains only one annotated gene, tribbles homolog 1 (TRIB1), which has not previously been implicated in lipoprotein metabolism. Here we demonstrate a role for Trib1 as a regulator of lipoprotein metabolism in mice. Hepatic-specific overexpression of Trib1 reduced levels of plasma TG and cholesterol by reducing VLDL production; conversely, Trib1-knockout mice showed elevated levels of plasma TG and cholesterol due to increased VLDL production. Hepatic Trib1 expression was inversely associated with the expression of key lipogenic genes and measures of lipogenesis. Thus, we provide functional evidence for what we believe to be a novel gene regulating hepatic lipogenesis and VLDL production in mice that influences plasma lipids and risk for myocardial infarction in humans.     

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR(-/-) mice

Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR(-/-)) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRα (Lenti-SP-LXRα) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRα mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-α. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRα gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR(-/-) mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.     

Malondialdehyde (MDA) and protein carbonyl (PCO) levels as biomarkers of oxidative stress in subjects with familial hypercholesterolemia

ObjectiveFamilial hypercholesterolemia (FH) is clinically characterized by elevated total and low-density lipoprotein (LDL) cholesterol levels in plasma, which has high risk for developing atherosclerosis. Increased oxidative stress (OS) and FH have been related to atherosclerosis. The study aims to evaluate oxidative stress in patients with hypercholesterolemia by measuring lipid peroxidation and protein carbonyl (PCO) levels in these patients. PCO in these patients may provide a new diagnostic biomarker for oxidative damage in atherosclerosis.Design and methodTotal cholesterol (Tc), low-density lipoprotein-cholesterol (LDL-c), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-c), lipoprotein(a) (Lp-a) levels and carotid intima-media thickness were measured to evaluate characteristics of patients (11 homozygous and 25 heterozygous) with FH. 25 age–gender–BMI matched healthy control subjects were included in the study for comparison.ResultsMDA and PCO levels were significantly higher in homozygous patients compared with those of heterozygous and controls and it was found that they are positively correlated with LDL-c, Tc, Lp-a and IMT while negatively correlated with HDL-c. The heterozygous group also had significantly higher MDA and PCO levels compared with controls.ConclusionThe data obtained could be important for understanding the alterations presented by FH and could be related to their increased risk of developing atherosclerosis. To our knowledge, measurements of PCO in patients with FH are not recorded before and this may be used as a biomarker for protein oxidation, which may play a role in the increased cardiovascular risk of patients with FH.