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Biomedical subjects

M John Chapman

Publications and source records attributed to M John Chapman.

At least 19 recordsLinked to original sources
PubMed2006

From pathophysiology to targeted therapy for atherothrombosis: a role for the combination of statin and aspirin in secondary prevention.

Atherothrombosis results from direct interaction between the atherosclerotic plaque and arterial thrombosis, and underlies most forms of cardiovascular disease (CVD). The pathophysiology of atherosclerosis is now recognised to involve endothelial dysfunction and dyslipidemia with cholesterol accumulation, as well as critical immuno-inflammatory and apoptotic dimensions. Erosion or rupture of a vulnerable, lipid-rich, inflammatory atherosclerotic plaque triggers the formation of a platelet-rich thrombus that may partially or completely occlude the artery, with resultant clinical scenarios including stable and unstable angina, acute myocardial infarction (MI) and ischaemic stroke. Insight into the pathophysiology of atherothrombosis indicates that an integrated risk factor approach, focusing particularly on management of dyslipidaemia (with a statin) and thrombosis (with aspirin), may constitute an optimal therapeutic approach. Both agents have established roles in secondary prevention. Statin action on atherogenic lipoproteins mediates plaque stabilisation, modification of plaque morphology and attenuation of inflammation, and may lead to plaque regression, while aspirin reduces platelet activation and aggregation, decreases release of inflammatory cytokines at sites of vascular injury and attenuates vasoconstriction. Given these complementary modes of action, this combination would be a logical choice for reducing atherothrombotic risk in patients with CVD. Meta-analysis of 5 major clinical studies has demonstrated that the combination of pravastatin plus aspirin was significantly more effective than either agent alone in reducing the relative risk of key cardiovascular endpoints including MI and ischaemic stroke. This combination may therefore represent an important, cost-efficient therapeutic approach to reduction of cardiovascular risk and prevention of recurrent events in stable CVD.

Animals↗
PubMed2006

Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues.

Scavenger receptor SR-BI has been implicated in HDL-dependent atheroprotective mechanisms. We report the generation of an SR-BI conditional knockout mouse model in which SR-BI gene targeting by loxP site insertion produced a hypomorphic allele (hypomSR-BI). Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-fold elevation in plasma total cholesterol (TC) levels. Cre-mediated SR-BI gene inactivation of the hypomorphic SR-BI allele in hepatocytes (hypomSR-BI-KO(liver)) was associated with high plasma TC concentrations, increased plasma free cholesterol/TC (FC/TC) ratio, and a lipoprotein-cholesterol profile typical of SR-BI-/- mice. Plasma TC levels were increased 2-fold in hypomSR-BI and control mice fed an atherogenic diet, whereas hypomSR-BI-KO(liver) and SR-BI-/- mice developed severe hypercholesterolemia due to accumulation of FC-rich, VLDL-sized particles. Atherosclerosis in hypomSR-BI mice was enhanced (2.5-fold) compared with that in controls, but to a much lower degree than in hypomSR-BI-KO(liver) (32-fold) and SR-BI-/- (48-fold) mice. The latter models did not differ in either plasma lipid levels or in the capacity of VLDL-sized lipoproteins to induce macrophage cholesterol loading. However, reduced atherosclerosis in hypomSR-BI-KO(liver) mice was associated with decreased lesional macrophage content as compared with that in SR-BI-/- mice. These data imply that, in addition to its major atheroprotective role in liver, SR-BI may exert an antiatherogenic role in extrahepatic tissues.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2006

Apolipoprotein E knockout mice over-expressing human tissue inhibitor of metalloproteinase 1 are protected against aneurysm formation but not against atherosclerotic plaque development.

AIMS: We investigated the effect of plasma levels of human tissue inhibitor of metalloproteinase (hTIMP)-1 on arterial lesion development and aneurysm formation in apolipoprotein-E-deficient mice (ApoE(-/-)). METHODS: Control and transgenic mice were fed either a chow diet or a high-fat diet for 90 and 180 days. RESULTS: hTIMP-1 has a tendency to decrease atherosclerotic lesions, but did not attain significance (approximately 6% reduction in hTIMP-1(+/+), p = 0.075, and approximately 4% in hTIMP-1(+/0), p = 0.088 vs. control). Immunohistological and histological analyses revealed a reduction in macrophage accumulation (23% of control in hTIMP(+/0), p = 0.065, and 49% of control in hTIMP(+/+), p < 0.05) but not in collagen degradation within the lesion in transgenic mice. Moreover, elastin degradation in sites of pseudo-microaneurysms was reduced in transgenic mice (37% of control in hTIMP-1(+/0), p < 0.05, and 50% of control in hTIMP-1(+/+), p < 0.05). DNA array analysis of matrix metalloproteinase (MMP) expression followed by real-time PCR quantification revealed a significant up-regulation of MMP-3, MMP-12 and MMP-13 in arterial lesions of ApoE(-/-) mice fed a high-fat diet in comparison with the same mice fed a chow diet. CONCLUSION: These data show that hTIMP-1 reduces aneurysm formation in ApoE(-/-) mice but does not protect them against the development of arterial lesions.

Aneurysm↗
PubMed2006

Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease.

Innovative pharmacological approaches to raise anti-atherogenic high-density lipoprotein-cholesterol (HDL-C) are currently of considerable interest, particularly in atherogenic dyslipidemias characterized by low levels of HDL-C, such as type 2 diabetes, the metabolic syndrome, and mixed dyslipidemia, but equally among individuals with or at elevated risk for premature cardiovascular disease (CVD). Epidemiological and observational studies first demonstrated that HDL-C was a strong, independent predictor of coronary heart disease (CHD) risk, and suggested that raising HDL-C levels might afford clinical benefit. Accumulating data from clinical trials of pharmacological agents that raise HDL-C levels have supported this concept. In addition to the pivotal role that HDL-C plays in reverse cholesterol transport and cellular cholesterol efflux, HDL particles possess a spectrum of anti-inflammatory, anti-oxidative, anti-apoptotic, anti-thrombotic, vasodilatory and anti-infectious properties, all of which potentially contribute to their atheroprotective nature. Significantly, anti-atherogenic properties of HDL particles are attenuated in common metabolic diseases that are characterized by subnormal HDL-C levels, such as type 2 diabetes and metabolic syndrome. Inhibition of cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism and transport, constitutes an innovative target for HDL-C raising. In lipid efficacy trials, 2 CETP inhibitors-JTT-705 and torcetrapib-induced marked elevation in HDL-C levels, with torcetrapib displaying greater efficacy. Moreover, both agents attenuate aortic atherosclerosis in cholesterol-fed rabbits. Clinical trial data demonstrating the clinical benefits of these drugs on atherosclerosis and CHD are eagerly awaited.

Amides↗
PubMed2006

Carotid atherosclerosis is not related to past tuberculosis in hypercholesterolemic patients.

BACKGROUND: Tuberculosis is a chronic recurrent infection and inflammation is part of the disease which may remain undiagnosed for months. Furthermore immunization with recombinant heat shock protein-65-rich mycobacterium tuberculosis increased atherogenesis in hypercholesterolemic animal models. OBJECTIVE: To investigate the potential interrelationships between past tuberculosis with carotid and femoral atherosclerosis in hypercholesterolemic patients. DESIGN AND SETTING: Case control study in a university hospital. PATIENTS: Two groups of hypercholesterolemic patient group (n=147) studied in a cardiovascular prevention unit during the same quarter, age (+/-1 year) and sex-matched. The first group presented a history of tuberculosis in the past and the second group never. METHODS: Atherosclerosis was assessed by carotid and femoral external echography. Measurements of maximum plaque diameter were done in longitudinal planes, and the extent of atherosclerosis was graded according to the most severe visible changes on the scanned arteries. RESULTS: The frequency and the distribution of atherosclerosis was similar in the two groups, whatever the arterial site explored, carotid or femoral. None of the clinical and biological studied variables were different between the two groups of patients. CONCLUSION: Past tuberculosis is not associated with increased frequency of atherosclerotic lesions in hypercholesterolemic patients.

Carotid Artery Diseases↗
PubMed2006

Alterations in lipoprotein defense against oxidative stress in metabolic syndrome.

Metabolic syndrome (MetS) is a high-risk condition for premature atherosclerotic vascular disease. Patients with MetS display a lipoprotein profile in which dense low-density lipoproteins (LDL), which are more susceptible to oxidation, predominate. Oxidation of lipoproteins can be attenuated in vivo by enzymatic and nonenzymatic antioxidant defenses, but high-density lipoproteins (HDL) play a key role in the protection of LDL from oxidation. Such activity depends on the presence of apolipoproteins (apoA-I, apoA-II, apoA-IV, apoE) and enzymes (paraoxonase 1, platelet activating factor-acetylhydrolase, lecithin:cholesterol acyltransferase, glutathione peroxidase). The impairment of HDL antioxidative activity in MetS is partly related to an enrichment of small HDL in triglycerides and their depletion in cholesteryl esters, to the replacement of apoA-I by serum amyloid A, and to glycation and oxidation of apoA-I. Therapeutic normalization of the quantity and the quality of HDL particles may constitute a novel approach to attenuate atherosclerosis and cardiovascular risk in MetS.

Atherosclerosis↗
PubMed2006

Antiatherogenic small, dense HDL--guardian angel of the arterial wall?

Our understanding of the relationship between the atheroprotective activities of HDL and heterogeneity of HDL particles has advanced greatly. HDL particles are highly heterogeneous in structure, intravascular metabolism and antiatherogenic activity. In this review, we discuss new findings on the antiatherogenic properties of HDL particles. Small, dense HDL possesses potent antioxidative activity but this is compromised under conditions of atherogenic dyslipidemia. HDL functional deficiency frequently coincides with reductions in HDL-cholesterol concentration and alterations in HDL metabolism and structure. Formation of small, dense HDL particles with attenuated antiatherogenic activity can be mechanistically related to HDL enrichment in triglycerides and in serum amyloid A, depletion of cholesteryl esters, covalent modification of HDL apolipoproteins and attenuated antiatherogenic function of apolipoprotein AI. Low circulating levels of HDL cholesterol might, therefore, be associated with the defective functionality of small HDL particles of abnormal structure and composition. In common metabolic diseases, such as type 2 diabetes and metabolic syndrome, deficiency of HDL particle number and function favor accelerated atherosclerosis. Therapeutic normalization of the quantity, quality and biological activities of HDL particles thus represents a novel approach to attenuating atherosclerosis in dyslipidemic individuals with metabolic disease. Cholesteryl ester transfer protein inhibitors, nicotinic acid, reconstituted HDL and other HDL-raising agents are being investigated. Induction of selective increase in the circulating concentrations of small, dense HDL3 particles with increased antiatherogenic activity seems especially promising, particularly for therapy of atherogenic dyslipidemia.

Biomarkers↗
PubMed2006

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Apolipoproteins B↗
PubMed2006

Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis.

High-density lipoproteins (HDL) possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, and anti-oxidative and anti-inflammatory activities. Plasma HDL particles are highly heterogeneous in physicochemical properties, metabolism, and biological activity. Within the circulating HDL particle population, small, dense HDL particles display elevated cellular cholesterol efflux capacity, afford potent protection of atherogenic low-density lipoprotein against oxidative stress and attenuate inflammation. The antiatherogenic properties of HDL can, however be compromised in metabolic diseases associated with accelerated atherosclerosis. Indeed, metabolic syndrome and type 2 diabetes are characterized not only by elevated cardiovascular risk and by low HDL-cholesterol (HDL-C) levels but also by defective HDL function. Functional HDL deficiency is intimately associated with alterations in intravascular HDL metabolism and structure. Indeed, formation of HDL particles with attenuated antiatherogenic activity is mechanistically related to core lipid enrichment in triglycerides and cholesteryl ester depletion, altered apolipoprotein A-I (apoA-I) conformation, replacement of apoA-I by serum amyloid A, and covalent modification of HDL protein components by oxidation and glycation. Deficient HDL function and subnormal HDL-C levels may act synergistically to accelerate atherosclerosis in metabolic disease. Therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and quality of HDL particles is the target of innovative pharmacological approaches to HDL raising, including inhibition of cholesteryl ester transfer protein, enhanced lipidation of apoA-I with nicotinic acid and infusion of reconstituted HDL or apoA-I mimetics. A preferential increase in circulating concentrations of HDL particles possessing normalized antiatherogenic activity is therefore a promising therapeutic strategy for the treatment of common metabolic diseases featuring dyslipidemia, inflammation, and premature atherosclerosis.

Animals↗
PubMed2006

One third of the variability in HDL-cholesterol level in a large dyslipidaemic population is predicted by age, sex and triglyceridaemia: The Paris La Pitié Study.

OBJECTIVE: The objective of this study was to identify key determinants of high-density lipoprotein-cholesterol (HDL-C) level, including subclinical inflammation and insulin resistance, and to determine the prevalence of a low HDL-C phenotype in dyslipidaemic patients at high cardiovascular risk. METHODS: In a cross-sectional study, we assessed the prevalence of low HDL-C phenotypes in 14 667 dyslipidaemic patients attending our specialised lipid clinic and evaluated the potential relationships between HDL-C level and 16 clinical and biological parameters. RESULTS: In univariate analysis, women exhibited higher plasma concentrations of HDL-C as compared with men. Levels of triglycerides, fasting blood glucose, uric acid, waist circumference, body mass index, high sensitivity C-reactive protein (hs-CRP), insulin resistance (as HOMA-IR index) and smoking were all negatively correlated with HDL-C, whereas age was positively correlated with HDL-C levels. Moderate drinkers (10-30 g/day) displayed higher HDL-C concentrations as compared with abstinent subjects; in contrast, consumption of more than 30 g alcohol/day was associated with a further non-significant elevation of HDL-C levels as compared to moderate drinkers. Multivariate analysis identified eight independent correlates of HDL-C. Age, sex and TG accounted for 37% of variability in HDL-C; modifiable factors including waist circumference, alcohol consumption and smoking, in addition to HOMA-IR and hs-CRP, accounted for an additional 5% of the variability in HDL-C. Using a cut-off of 40 mg/dL (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women, 33% and 28% of men and women displayed low levels of HDL-C. CONCLUSION: Eight independent determinants of HDL-C account for 41% of variability in HDL-C in our dyslipidaemic population. Three of them, i.e. age, sex and degree of triglyceridaemia accounted for more than one third of such variability. The high prevalence of low HDL-C phenotypes in dyslipidaemic patients at elevated cardiovascular risk emphasises the need for both lifestyle and pharmacological strategies of intervention to raise HDL-C.

Adult↗
PubMed2005

Elevated serum levels of proinflammatory cytokines and biomarkers of matrix remodeling in never-treated patients with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism, whose origin involves mutations in the gene coding for the low-density lipoprotein receptor protein. Although FH is monogenic, wide variation occurs in the onset and severity of atherosclerosis in these patients. METHODS: Since data on levels of inflammatory proteins and/or active factors in FH patients who have never received lipid-lowering treatment are lacking, serum levels of MMP-3, active MMP-9 and TIMP-1 as well as pro-inflammatory cytokines (TNF-alpha, IL-18) were determined in never-treated homozygous FH Moroccan patients (n=4) and compared to those of heterozygous FH subjects (n=7) and of healthy control subjects (n=5). RESULTS: When compared to controls, homozygous FH patients exhibited levels of active MMP-9 and TIMP-1 (p<0.05), and of both high sensitive-CRP and IL-18 which were significantly elevated (p<0.05 and p<0.01, respectively). In heterozygous FH patients, intermediate values between FH homozygotes and healthy controls were observed for these markers, with the exception of MMP-9 activity whose levels were significantly elevated (p<0.05). Multivariate analysis revealed a positive correlation between apolipoprotein B, TIMP-1 and IL-18 levels, and between hs-CRP and IL-18 (p<0.01). CONCLUSIONS: Although the sample size of this FH group was limited, our data suggest that nontreated homozygous FH patients, and to a lesser degree heterozygous FH patients, exhibit not only a markedly proinflammatory vascular state but also pronounced extracellular matrix remodeling, as reflected by elevated circulating levels of inflammatory cytokines and MMPs.

Adolescent↗
PubMed2005

Functional interaction between -629C/A, -971G/A and -1337C/T polymorphisms in the CETP gene is a major determinant of promoter activity and plasma CETP concentration in the REGRESS Study.

Cholesteryl ester transfer protein (CETP) plays a key role in the determination of high-density lipoprotein (HDL) levels via its action on intravascular HDL metabolism. The TaqIB polymorphism of the CETP gene is associated with plasma CETP and high-density lipoprotein cholesterol (HDL-C) levels and with premature coronary artery disease. Such associations appear to result from linkage disequilibrium between TaqIB and other functional polymorphisms. To date, only one functional promoter variant, which may explain the effects of TaqIB, has been identified at position -629 in the CETP gene. Here we describe a C/T polymorphism located at position -1337 in the human CETP gene (C allele frequency: 0.684), which is significantly associated with plasma HDL-C and CETP levels (P=0.0001 and P<0.0001, respectively). Transient transfection of a reporter gene construct containing the CETP promoter from -1707/+28 in liver cells (HepG2) revealed that the -1337T allele was expressed to a significantly lower degree (-34%, P<0.0001) than the -1337C allele. In addition, we clearly demonstrated that the -971G/A polymorphism is functional and that its functionality is intimately linked to the presence of the -1337 site. In vitro evaluation of potential interaction between -1337C/T and other functional variants of the CETP gene (-971G/A and -629C/A) demonstrated that these three functional CETP promoter polymorphisms can interact together to determine the overall activity of the CETP gene and thus contribute significantly to variation in plasma CETP mass concentration.

Aged↗
PubMed2005

Thyroid hormone regulates the hypotriglyceridemic gene APOA5.

The apolipoprotein AV gene (APOA5) is a key determinant of plasma triglyceride levels, a major risk factor for coronary artery disease and a biomarker for the metabolic syndrome. Since thyroid hormones influence very low density lipoprotein triglyceride metabolism and clinical studies have demonstrated an inverse correlation between thyroid status and plasma triglyceride levels, we examined whether APOA5 is regulated by thyroid hormone. Here we report that 3,5,3'-triiodo-L-thyronine (T3) and a synthetic thyroid receptor beta (TRbeta) ligand increase APOA5 mRNA and protein levels in hepatocytes. Our data revealed that T3-activated TR directly regulates APOA5 promoter through a functional direct repeat separated by four nucleotides (DR4). Interestingly, we show that upstream stimulatory factor 1, a transcription factor associated with familial combined hyperlipidemia and elevated triglyceride levels in humans, and upstream stimulatory factor 2 cooperate with TR, resulting in a synergistic activation of APOA5 promoter in a ligand-dependent manner via an adjacent E-box motif. In rats, we observed that apoAV levels declines with thyroid hormone depletion but returned to normal levels upon T3 administration. In addition, treatments with a TRbeta-selective agonist increased apoAV and diminished triglyceride levels. The identification of APOA5 as a T3 target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis. Additionally, these data suggest that TRbeta may be a potential pharmacological target for the treatment of hypertriglyceridemia.

Amino Acid Motifs↗
PubMed2005

A normotriglyceridemic, low HDL-cholesterol phenotype is characterised by elevated oxidative stress and HDL particles with attenuated antioxidative activity.

OBJECTIVE: Low levels of high density lipoprotein-cholesterol (HDL-C) are highly prevalent in subjects presenting premature atherosclerosis. It is indeterminate as to whether high cardiovascular risk in low HDL-C subjects occurs concomitantly with elevated oxidative stress and/or with biologically dysfunctional HDL particles. METHODS AND RESULTS: Systemic oxidative stress (as plasma 8-isoprostanes) was 2.3-fold elevated (p<0.05) in normocholesterolemic, normotriglyceridemic, normoglycemic low HDL-C subjects (plasma HDL-C, <40 mg/dL; n=8) as compared to normolipidemic controls (n=15). HDL subfractions (HDL2b, 2a, 3a, 3b and 3c) isolated by density gradient ultracentrifugation from low HDL-C subjects displayed significantly lower (-21 to -43%, p<0.05) specific antioxidative activity (sAA; capacity to protect LDL from oxidation on a unit particle mass or on a particle number basis) as compared to controls. Altered chemical composition (core triglyceride enrichment, cholesteryl ester depletion) paralleled antioxidative dysfunction of HDL subfractions. Plasma 8-isoprostane levels negatively correlated with sAA of HDL subfractions and positively correlated with the total cholesterol/HDL-C ratio, which was significantly elevated in the low HDL-C phenotype. CONCLUSIONS: Low HDL-C subjects display elevated oxidative stress and possess HDL particle subspecies with attenuated intrinsic antioxidative activity which is intimately related to their altered chemical composition.

Adult↗
PubMed2005

Beyond the statins: new therapeutic perspectives in cardiovascular disease prevention.

Reduction of low-density lipoprotein cholesterol (LDL-C) with statin therapy is currently identified in treatment guidelines as the primary focus for patients with or at risk of coronary heart disease (CHD). Yet despite effective statin therapy there is still an unacceptably high residual coronary risk. A substantial proportion of patients with CHD have mixed dyslipidemia, including low levels of high-density lipoprotein cholesterol (HDL-C), an independent and predictive risk factor for CHD. Although effective in reducing LDL-C, statin therapy has only modest effects in raising HDL-C. Fibrate therapy is an alternative lipid-modifying strategy, and is effective in reducing CHD mortality and morbidity, with the magnitude of clinical benefit similar to statin therapy. Multi-drug therapy with complementary mechanisms of action has been proposed as a means of improving lipid-modifying efficacy. Nicotinic acid is the most potent agent for increasing HDL-C and also substantially reduces LDL-C and triglycerides. Addition of nicotinic acid to statin therapy would be a logical management approach, given the potential for complementary therapeutic benefit. The clinical benefits of this combination are supported by the results of the HDL Atherosclerosis Treatment Study, which showed reduction of 60-90% in the incidence of major coronary events when both agents were administered. In addition, combination treatment led to angiographic regression of stenosis, compared with placebo, rather than slowed progression as previously reported with statin monotherapy. Given that the prevalence of low HDL-C, particularly amongst individuals with CHD, is higher than previously anticipated, combining nicotinic acid and a statin represents an innovative approach to further reducing CHD risk.

Cardiovascular Diseases↗