Lipids and atherosclerosis.

Atherosclerosis is the leading cause of death in North America and within the next two decades will be the leading cause worldwide. Atherosclerosis is characterized by vascular obstruction from the deposits of plaque, resulting in reduced blood flow. Plaque rupture and the consequent thrombosis may lead to sudden blockage of the arteries and cause heart attack. High serum lipid levels, especially the elevated level of low-density lipoprotein (LDL), have been shown to be strongly related to the development of atherosclerosis. It is generally accepted that atherosclerotic lesions are initiated via an enhancement of LDL uptake by monocytes and macrophages. In the liver, uptake of plasma LDL is mediated via specific LDL receptors, but a scavenger receptor system is employed by macrophages. Plasma LDL must be modified prior to uptake by macrophages. Analysis of the lipid content in the oxidatively modified LDL from hyper lipidemic patients revealed that the level of lysophosphatidylcholine was greatly elevated, and the high level of the lysolipid was shown to impair the endothelium-dependent relaxation of the blood vessels. In a separate study, we showed that a high level of homocysteine caused the increase in cholesterol production and apolipoprotein B-100 secretion in hepatic cells. Statins have been used effectively to control the production of cholesterol in the liver, and recently, ezetimibe has been shown to supplement the efficacy of statins by inhibiting cholesterol absorption. The factor of elevated levels of triglyceride-rich lipoproteins in association with depressed high-density lipoproteins, usually in the context of insulin resistance, is an important contributor to atherosclerosis and can be effectively treated with fibric acid derivatives. In hyperhomocysteinemia, folic acid supplements may have a role in the control of cholesterol by reducing the plasma homocysteine level.     

载脂蛋白亚型与糖尿病合并冠心病的相关性研究

目的:探讨载脂蛋白亚型与糖尿病合并冠脉病变严重程度相关性,为预防及治疗糖尿病伴发的动脉粥样硬化性疾病提供新的依据。方法:选取440名心内科患者,根据冠脉造影有无冠脉狭窄及是否合并糖尿病分为四组:冠脉内膜光滑组94人(A组);单纯冠脉狭窄组108人(B组);糖尿病合并冠脉狭窄组共184人(C组);糖尿病冠脉无狭窄组44人(D组),记录患者空腹血糖、餐后血糖、传统血脂脂谱、载脂蛋白A(apoA)、载脂蛋白B(apoB)及两者的比值(apoB/apoA);采用Gensini评分比较传统血脂、apoA、apoB及与Gensini积分值的相关性。结果:与正常对照组比较,糖尿病冠脉无狭窄组apoB、apoB/apoA、LDL和TG升高,apoA和HDL降低,B组和C组apoA与Gensini积分值存在负相关(P=0.01570.05);apoB;apoB/apoA与Gensini积分值存在正相关(P0.0001);两组中,apoB与Gensini积分值相关系数最大(r=0.85795,0.85941),且apoB与Gensini积分值的相关性都强于LDL与积分值的相关性。结论:在糖尿病患者预测心血管风险上,apoB,apoA,apoB/apoA的测定可能优于传统的血脂指标。     

The influence of thyroid hormones on homocysteine and atherosclerotic vascular disease

Several reports have appeared in the literature proving that hypothyroidism is associated with increased risk for cardiovascular disease, especially coronary heart disease. This increased risk for premature atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. Hypothyroid patients have increased diastolic blood pressure (as a result of increased systemic vascular resistance), altered lipid profile (elevated levels of total cholesterol, LDL-cholesterol and apolipoprotein B). More recently homocysteine, C-reactive protein, increased arterial stiffness, endothelial dysfunction and altered coagulation parameters have been recognized as a "new" risk factors for atherosclerosis in patients with thyroid hormone deficiency. The plasma total homocysteine concentration, an independent risk factor for atherosclerosis, is moderately elevated in overtly hypothyroid patients and it decreases with thyroid replacement therapy. Several experimental study have shown that hypothyroidism affects folate metabolism and the enzymes involved in the remetylation pathway of homocysteine (particularly 5,10-methylenotetrahydrofolate reductase - MTHFR). In hypothyroid condition the hepatic activity of flavoenzyme - MTHFR, is decreased. Thyroid hormone may affect the availability of FMN and FAD - necessary for stabilizing MTHFR. An impairment of enzyme involved in transsulfuration pathway is suggested. The increased serum creatinine level in hypothyroidism probably reflects a reduced glomerular filtration rate, which is linked to impaired renal homocysteine clearance and hyperhomocysteinemia.     

The effect of taurine on cholesterol metabolism

The elevated plasma cholesterol level, in particular, LDL cholesterol is regarded as an important risk factor for the development of atherosclerosis and coronary artery disease. A number of studies provide the evidence that taurine has the efficient action to reduce plasma and liver cholesterol concentrations, especially to decrease VLDL and LDL cholesterol in hypercholesterolemia animal induced by high cholesterol diet. Cholesterol lowering effect of taurine is actually involved in the regulatory mechanism of cholesterol and bile acid homeostasis that mediated by CYP7A1, which has become a biomarker for cholesterol metabolism and itself is also regulated by several factors and nuclear receptors. This review summarizes the change of cholesterol concentration in metabolism observed in feeding studies of hypercholesterolemia animal dealing with taurine, and then, addresses the possible metabolic and molecular mechanisms of cholesterol lowering effect by taurine in three aspects, cholesterol clearance from blood circulation, bioconversion of cholesterol to bile acid in liver, and excretion of cholesterol and bile acid from intestine.     

ACAT2 stimulates cholesteryl ester secretion in apoB-containing lipoproteins

Previous studies in nonhuman primates revealed a striking positive correlation between liver cholesteryl ester (CE) secretion rate and the development of coronary artery atherosclerosis. CE incorporated into hepatic VLDL is necessarily synthesized by ACAT2, the cholesterol-esterifying enzyme in hepatocytes. We tested the hypothesis that the level of ACAT2 expression, in concert with cellular cholesterol availability, affects the CE content of apolipoprotein B (apoB)-containing lipoproteins. In a model system of lipoprotein secretion using COS cells cotransfected with microsomal triglyceride transfer protein and truncated forms of apoB, ACAT2 expression resulted in a 3-fold increase in microsomal ACAT activity and a 4-fold increase in the radiolabeled CE content of apoB-lipoproteins. After cholesterol-cyclodextrin (Chol-CD) treatment, CE secretion was increased by 27-fold in ACAT2-transfected cells but by only 7-fold in control cells. Chol-CD treatment also caused the percentage of CE in the apoB-lipoproteins to increase from 3% to 33% in control cells and from 16% to 54% in ACAT2-transfected cells. In addition, ACAT2-transfected cells secreted 3-fold more apoB than control cells. These results indicate that under all conditions of cellular cholesterol availability tested, the relative level of ACAT2 expression affects the CE content and, hence, the potential atherogenicity, of nascent apoB-containing lipoproteins.     

Studies on the expression of genes encoding apolipoproteins B100 and B48 and the low density lipoprotein receptor in nonhuman primates. Comparison of dietary fat and cholesterol

African green monkeys were fed diets containing low and moderate cholesterol concentrations with either polyunsaturated or unsaturated fat as 40% of calories. Plasma total cholesterol, low density lipoprotein (LDL) cholesterol, and apoB concentrations generally were higher in animals fed (a) the higher dietary cholesterol concentration and (b) saturated fat. At necropsy, liver and intestine were removed, and measurement of mRNAs for LDL receptors (liver) and for apolipoprotein B (liver and intestine) was done. Monkey small intestine mucosa made exclusively apoB48 while the liver made only apoB100, although apoB mRNA in both tissues was the same size (14 kilobases). No dietary cholesterol or fat effects were found for apoB mRNA abundance in the liver, while the animals fed the higher dietary cholesterol level had 50% lower levels of hepatic LDL receptor mRNA. In a separate group of animals, livers were perfused and the rate of apoB secretion was measured. No dietary fat effect on apoB secretion rate was found, and no relationship between plasma LDL cholesterol concentration and the rate of hepatic apoB production existed. These findings support the idea that the dietary factors that increase LDL concentrations act by reducing clearance of apoB-containing particles rather than by increasing production of these lipoproteins. Hepatic LDL receptor mRNA was similar in abundance in polyunsaturated fat and saturated fat-fed animals, suggesting that the difference in plasma cholesterol concentration between these groups is not mediated via effects on LDL receptor mRNA abundance. The level of intestinal apoB mRNA was about 30% higher in animals fed the moderate dietary cholesterol concentration. Earlier studies have shown that more cholesterol is transported in chylomicrons from the intestine when dietary cholesterol levels are higher, and the increased intestinal apoB mRNA abundance may reflect increased intestinal cholesterol transport and chylomicron apoB48 production.     

Molecular mechanisms of cholesterol or homocysteine effect in the development of atherosclerosis: Role of vitamin E

The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidized low density lipoprotein. Some epidemiological studies have shown an association between high dietary intake and high serum concentrations of vitamin E and lower rates of ischemic heart disease. Cell culture studies have shown that alpha-tocopherol brings about inhibition of smooth muscle cell proliferation. This takes place via inhibition of protein kinase C activity. alpha-Tocopherol also inhibits low density lipoprotein induced smooth muscle cell proliferation and protein kinase C activity. The following animal studies showed that vitamin E protects development of cholesterol induced atherosclerosis by inhibiting protein kinase C activity in smooth muscle cells in vivo. Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promotes atherosclerotic plaque formation are not clearly defined. Earlier reports have been suggested that homocysteine exert its effect via H2O2 produced during its metabolism. To evaluate the contribution of homocysteine in the pathogenesis of vascular diseases, we examined whether the homocysteine effect on vascular smooth muscle cell growth is mediated by H2O2. We show that homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells in the presence of peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through the activation of an H2O2 independent pathway and accelerate the progression of atherosclerosis. The results indicate a cellular mechanism for the atherogenicity of cholesterol or homocysteine and protective role of vitamin E in the development of atherosclerosis.     

Pedigree and sib-pair linkage analysis suggest the apolipoprotein B gene is not the major gene influencing plasma apolipoprotein B levels.

Previous studies suggest that plasma apolipoprotein B-100 (apoB) level is strongly influenced by genetic factors. Characterizing alleles that influence plasma apoB level would help define genetic risk factors for coronary artery disease. This study examined the role of variability in the apolipoprotein B gene (APOB) in determining plasma apoB level. Twenty-three informative families from the Johns Hopkins Coronary Artery Disease Family Study were studied. Linkage analysis between three polymorphisms in the APOB gene (XbaI at codon 2488, MspI at codon 3611, and EcoRI at codon 4154) and a putative major gene with a codominant allele for elevated apoB levels gave evidence against linkage (LOD score of -7.9 at a recombination fraction of .001). None of the families had a LOD score greater than 0.5, while five families had a LOD score less than -0.5. Sib-pair analysis also showed no relationship between the proportion of genes identical by descent at the APOB locus and either crude or adjusted plasma apoB levels. Thus, in 23 informative families, there was no evidence for the presence, in APOB, of common alleles that influence plasma apoB levels. These results suggest that APOB is not the major locus influencing plasma apoB levels.     

Isolevuglandin-protein adducts in humans: products of free radical-induced lipid oxidation through the isoprostane pathway

A family of extremely reactive electrophiles, isolevuglandins (isoLGs), is generated in vivo by free radical-induced lipid oxidation and rearrangement of endoperoxide intermediates of the isoprostane pathway. Protein adducts of two different oxidized lipids, isoLGE(2) and iso[4]LGE(2), and the corresponding autoantibodies are present in human blood. Western blot analysis of a polyacrylamide gel electrophoresis gel detects several immunoreactive plasma proteins. Only a minor fraction of the isoLG-protein modifications is associated with low density lipoprotein since mean levels were decreased only 20-22% by immunoprecipitation of apolipoprotein B (apoB). Mean levels of both isoLGE(2) and iso[4]LGE(2)-protein adducts in plasma from patients with atherosclerosis (AS) (n=16) or end-stage renal disease (RD) (n=8) are about twice those in healthy individuals (n=25). These elevated levels are not related to variations in age, total cholesterol or apoB. A linear correlation (r=0.79) between plasma isoLGE(2) and iso[4]LGE(2)-protein adduct levels in all 49 individuals is consistent with a common free radical-induced mechanism for the production of both oxidized lipids in vivo. The correlation is even stronger (r=0.86) for patients with AS or RD. That isoLG-protein adduct levels are more strongly correlated with disease than are total cholesterol or apoB suggests an independent defect that results in an abnormally high level of oxidative injury associated with AS and RD.     

Association of homocysteine and methylene tetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India

The implications of the methylene tetrahydrofolate reductase (MTHFR) gene and the level of homocysteine in the pathogenesis of coronary artery disease (CAD) have been extensively studied in various ethnic groups. Our aim was to discover the association of MTHFR (C677T) polymorphism and homocysteine level with CAD in north Indian subjects. The study group consisted of 329 angiographically proven CAD patients, and 331 age and sex matched healthy individuals as controls. MTHFR (C677T) gene polymorphism was detected based on the polymerase chain reaction and restriction digestion with HinfI. Total homocysteine plasma concentration was measured using immunoassay. T allele frequency was found to be significantly higher in patients than in the control group. We found significantly elevated levels of mean homocysteine in the patient group when compared to the control group (p = 0.00). Traditional risk factors such as diabetes, hypertension, smoking habits, a positive family history and lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol), were found significantly associated through univariate analysis. Furthermore, multivariable logistics regression analysis revealed that CAD is significantly and variably associated with diabetes, hypertension, smoking, triglycerides and HDL-cholesterol. Our findings showed that MTHFR C677T polymorphism and homocysteine levels were associated with coronary artery disease in the selected population.     

Retina expresses microsomal triglyceride transfer protein: implications for age-related maculopathy

The principal extracellular lesions of age-related maculopathy (ARM), the leading cause of vision loss in the elderly, involve Bruch's membrane (BrM), a thin vascular intima between the retinal pigment epithelium (RPE) and its blood supply. With age, 80-100 nm solid particles containing esterified cholesterol (EC) accumulate in normal BrM, and apolipoprotein B (apoB) immunoreactivity is detectable in BrM- and ARM-associated lesions. Yet little evidence indicates that increased plasma cholesterol is a risk factor for ARM. To determine if RPE is capable of assembling its own apoB-containing lipoprotein, we examined RPE for the expression of microsomal triglyceride transfer protein (MTP), which is required for this process. Consistent with previous evidence for apoB expression, MTP is expressed in RPE, the ARPE-19 cell line, and, unexpectedly, retinal ganglion cells, which are neurons of the central nervous system. De novo synthesis and secretion of neutral lipid by ARPE-19 was supported by high levels of radiolabeled EC and triglyceride in medium after supplementation with oleate. Lipoprotein assembly and secretion is implicated as a constitutive retinal function and a plausible candidate mechanism involved in forming extracellular cholesterol-containing lesions in ARM. The pigmentary retinopathy and neuropathy of abetalipoproteinemia (Mendelian Inheritance of Man 200100; Bassen-Kornzwieg disease), which is caused by mutations in the MTP gene, may involve loss of function at the retina.     

ACTH decreases the expression and secretion of apolipoprotein B in HepG2 cell cultures

Administration of adrenocorticotropic hormone (ACTH) has been shown to decrease plasma concentrations of apolipoprotein B (apoB) containing lipoproteins, including lipoprotein(a), in man. However, the mechanism behind this hypolipidemic effect is unknown. This study aimed at distinguishing between the main possibilities (increased elimination or decreased production of lipoproteins) using HepG2 cell cultures. Addition of ACTH to the cell culture medium selectively down-regulated apoB mRNA expression and apoB secretion in a dose-dependent manner. At 100 pmol/liter ACTH, the apoB mRNA level was about 40% lower than in the untreated cells, and the secretion of apoB into the medium was decreased to a similar extent. The expression and secretion of other apolipoproteins (apoA-I, apoE, and apoM), however, were not affected by ACTH. Under normal culture conditions the level of secretion of apoB from HepG2 cells is quite low. In the presence of 0.4 mmol/liter oleic acid secretion of apoB increased 3-fold, but this phenomenon was not seen in ACTH-treated cells. Binding and internalization of radiolabeled low density lipoprotein (LDL) by HepG2 cell, as well as LDL-receptor mRNA and scavenger receptor B-I mRNA levels, were not influenced by ACTH. In conclusion, ACTH directly and selectively down-regulated the production and secretion of apoB in HepG2 cell cultures, suggesting that a principal mechanism behind the cholesterol-lowering effect of ACTH in vivo may be a decreased production rate of apoB-containing lipoproteins from the liver.     

Cholesterol and vitamins: revisited study

The link between low density lipoprotein and coronary heart disease has been widely studied. Oxidized LDL damages the artery wall, and a diet rich in vitamins and low in saturated fat and cholesterol may reduce this risk. Not only hypercholesterolemia but also low levels of high density lipoprotein cholesterol are critical risk factors for atherosclerosis and related diseases. It has been reported that high doses of B complex vitamin may be useful in lowering blood cholesterol and triglyceride levels in the body, however the use of this compound has been limited by an annoying flush and concern for toxicity. Niacin is a B-complex vitamin with anti-atherosclerotic properties and is an effective medication for raising high density lipoprotein. The combination of niacin with other lipid-lowering drugs, such as statins, reduces the dynamic of atherosclerosis disease. In addition, vitamin E is one of the most important lipid soluble anti-oxidants in humans, and reduces atherosclerosis plaque, coronary artery diseases and myocardial infarction. Vitamin E protects the integrity of membranes by inhibiting lipid peroxidation. In this study we revisited the interrelationship between cholesterol, low density lipoproteins and vitamins.     

Differential effects of oxidized LDL on apolipoprotein AI and B synthesis in HepG2 cells

Oxidized low-density lipoproteins (Ox-LDL) are key elements in atherogenesis. Apolipoprotein AI (apoAI) is an active component of the antiatherogenic high-density lipoproteins (HDL). In contrast, plasma apolipoprotein B (apoB), the main component of LDL, is highly correlated with coronary risk. Our results, obtained in HepG2 cells, show that Ox-LDL, unlike native LDL, leads to opposite effects on apoB and apoAI, namely a decrease in apoAI and an increase in apoB secretion as evaluated by [(3)H]leucine incorporation and specific immunoprecipitation. Parallel pulse-chase studies show that Ox-LDL impaired apoB degradation, whereas apoAI degradation was increased and mRNA levels were decreased. We also found that enhanced lipid biosynthesis of both triglycerides and cholesterol esters was involved in the Ox-LDL-induced increase in apoB secretion. Our data suggest that the increase in apoB and decrease in apoAI secretion may in part contribute to the known atherogenicity of Ox-LDL through an elevated LDL/HDL ratio, a strong predictor of coronary risk in patients.     

Synthesis and secretion of VLDL by rat hepatocytes--modulation by cholesterol and phospholipids.

The synthesis and secretion of apoB, the major protein component of very low density lipoprotein (VLDL) and low density lipoprotein (LDL), were studied using rat hepatocytes maintained in primary culture. Supplementation of hepatocytes with rat serum VLDL and LDL increased the production of apoB while delipidated lipoproteins had no significant effect, suggesting a role for lipids in the production of apoB. Addition of cholesterol to the culture medium also increased the production of apoB in a concentration-dependent manner. Pulse labelling followed by chase in presence of cholesterol indicated enhancement in apoB secretion. Mevinolin which inhibits cholesterol synthesis significantly reduced the secretion of apoB. The presence of phosphatidylcholine and phosphatidylethanolamine in the culture medium also increased the secretion of apoB into the medium. These data suggest that availability of lipids, particularly cholesterol, is an important determinant of apoB synthesis and secretion as VLDL.     

Fish oil decreases hepatic cholesteryl ester secretion but not apoB secretion in African green monkeys

Two groups of African green monkeys were fed diets containing 40% of calories as fat with half of the fat calories as either fish oil or lard. The fish oil-fed animals had lower cholesterol concentrations in blood plasma (33%) and low density lipoproteins (LDL) (34%) than did animals fed lard. Size and cholesteryl ester (CE) content of LDL, strong predictors of coronary artery atherosclerosis in monkeys, were significantly less for the fish oil-fed animals although the apoB and LDL particle concentrations in plasma were similar for both diet groups. We hypothesized that decreased hepatic CE secretion led to the smaller size and reduced CE content of LDL in the fish oil-fed animals. Hepatic CE secretion was studied using recirculating perfusion of monkey livers that were infused during perfusion with fatty acids (85% 18:1 and 15% n-3) at a rate of 0.1 mumol/min per g liver. The rate of cholesterol secretion was less (P = 0.055) for the livers of fish oil versus lard-fed animals (3.3 +/- 0.5 vs. 6.0 +/- 1.2 mg/h per 100 g, mean +/- SEM) but the rate of apoB secretion was similar for both groups (0.92 +/- 0.15 vs. 1.01 +/- 0.13 mg/h per 100 g, respectively). The hepatic triglyceride secretion rate was also less (P less than 0.05) for the fish oil-fed animals (8.3 +/- 2.5 vs. 18.3 +/- 4.4 mg/h per 100 g). Liver CE content was lower (P less than 0.006) in fish oil-fed animals (4.1 +/- 0.8 vs. 7.4 +/- 0.7 mg/g) and this was reflected in a lower (P less than 0.04) esterified to total cholesterol ratio of perfusate VLDL (0.21 +/- 0.045 vs. 0.41 +/- 0.06). The hepatic VLDL of animals fed fish oil had 40-50% lower ratios of triglyceride to protein and total cholesterol to protein. From these data we conclude that livers from monkeys fed fish oil secreted similar numbers of VLDL particles as those of lard-fed animals although the hepatic VLDL of fish oil-fed animals were smaller in size and relatively enriched in surface material and depleted of core constituents. Positive correlations between plasma LDL size and both hepatic CE content (r = 0.87) and hepatic VLDL cholesterol secretion rate (r = 0.84) were also found.(ABSTRACT TRUNCATED AT 400 WORDS)     

Homocysteine is positively associated with cytokine IL-18 plasma levels in coronary artery bypass surgery patients

Homocysteine, cytokines (IL-18, IL-6, IL-8) are involved in vascular inflammation and coronary artery disease. Homocysteine influences endothelial IL-6 and IL-8 cytokine expression and release, however, an association between homocysteine and IL-18 has not been previously investigated in endothelial/smooth muscle cells and or in coronary artery disease. We report in 9 coronary artery bypass surgery (CABG) patients a positive correlation r = 0.86 between homocysteine and IL-18 plasma levels (p < 0.05). Plasma IL-18 levels are significantly higher in those patients with elevated homocysteine compared to those with normal levels (p < 0.02; 153 +/- 19 pg/ml versus 116 +/- 14 pg/ml respectively). Our in vitro cell culture studies suggest that the source of IL-18 in CABG patients with elevated homocysteine is not from vascular smooth muscle or endothelial cells.     

Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation.

Hypercholesterolemia (HC) is a mary risk factor for the development of coronary heart disease. Coronary ion regulation, especially calcium, is thought to be important in coronary heart disease development; however, the influence of high dietary fat and cholesterol on coronary arterial smooth muscle (CASM) ion channels is unknown. The purpose of this study was to determine the effect of diet-induced HC on CASM voltage-gated calcium current (I(Ca)). Male miniature swine were fed a high-fat, high-cholesterol diet (40% kcal fat, 2% wt cholesterol) for 20-24 wk, resulting in elevated serum total and low-density lipoprotein cholesterol. Histochemistry indicated early atherosclerosis in large coronary arteries. CASM were isolated from the right coronary artery (>1.0 mm ID), small arteries ( approximately 200 microm), and large arterioles ( approximately 100 microm). I(Ca) was determined by whole cell voltage clamp. L-type I(Ca) was reduced approximately 30% by HC compared with controls in the right coronary artery (-5.29 +/- 0.42 vs. -7.59 +/- 0.41 pA/pF) but not the microcirculation (small artery, -8.39 +/- 0.80 vs. -10.13 +/- 0.60; arterioles, -10.78 +/- 0.93 vs. -11.31 +/- 0.95 pA/pF). Voltage-dependent activation was unaffected by HC in both the macro- and microcirculation. L-type voltage-gated calcium channel (Ca(v)1.2) mRNA and membrane protein levels were unaffected by HC. Inhibition of I(Ca) by HC was reversed in vitro by the cholesterol scavenger methyl-beta-cyclodextrin and mimicked in control CASM by incubation with the cholesterol donor cholesterol:methyl-beta-cyclodextrin. These data indicate that CASM L-type I(Ca) is decreased in large coronary arteries in early stages of atherosclerosis, whereas I(Ca) in the microcirculation is unaffected. The inhibition of calcium channel activity in CASM of large coronary arteries is likely due to increases in membrane free cholesterol.     

同型半胱氨酸及甲状腺功能在他汀致冠心病患者肝功能异常中的研究

目的:研究同型半胱氨酸及甲状腺功能与他汀致冠心病患者肝功能异常的相关性。方法:服用阿托伐他汀钙(20mg,1次/日)后1-3个月肝功能正常组(ALT和AST均正常者)300例;肝功能轻度异常组(ALT或/和AST升高3倍以下者)300例;肝功能重度异常组(ALT或/和AST升高3倍以上者)300例。在转氨酶重度升高组中选取停用他汀药观察组和加用CoQ10(20mg,3次/日)治疗组各100例,对比两组转氨酶下降情况。结果:PCI术后服用他汀类药物治疗1-3个月后出现肝功能异常的冠心病患者,同型半胱氨酸水平升高,甲状腺功能降低;肝功能的异常与年龄及饮酒有相关性。转氨酶重度升高患者中,加用CoQ10治疗组较仅停药组转氨酶显著下降。结论:阿托伐他汀钙引起的冠心病患者同型半胱氨酸水平升高及甲状腺功能下降与肝功能损伤有明显相关性。CoQ10可显著降低转氨酶水平。