Publications by authors named "Vincent Durlach"

18 Publications

  • Page 1 of 1

Smoking and diabetes interplay: A comprehensive review and joint statement.

Diabetes Metab 2022 Jun 29;48(6):101370. Epub 2022 Jun 29.

Outpatient Addiction Center, Georges Pompidou European Hospital, AP-HP, Sorbonne Paris Cité, Paris, France.

Evidence shows that smoking increases the risk of pre-diabetes and diabetes in the general population. Among persons with diabetes, smoking has been found to increase the risk of all-cause mortality and aggravate chronic diabetic complications and glycemic control. The current paper, which is a joint position statement by the French-Speaking Society on Tobacco (Société Francophone de Tabacologie) and the French-Speaking Society of Diabetes (Société Francophone du Diabète), summarizes the data available on the association between smoking and diabetes and on the impact of smoking and smoking cessation among individuals with type 1, type 2, and gestational diabetes mellitus. It also provides evidence-based information about the pharmacological and behavioral strategies for smoking cessation in these patients.
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http://dx.doi.org/10.1016/j.diabet.2022.101370DOI Listing
June 2022

[Lipoprotein (a) :NSFA consensus].

Rev Prat 2022 Feb;72(2):123-129

Université de Paris, Inserm, Innovative Therapies in Haemostasis, Paris, France.

LIPOPROTEIN(a) : NSFA CONSENSUS Lipoprotein(a), first described in 1963, consists of a low-density lipoprotein (LDL) associated with apolipoprotein(a) [apo(a)] which has a structural similarity with plasminogen but does not have fi-brinolytic activity. This complex structure determines the prothrom¬botic and antifibrinolytic action of high concentrations of Lp(a) and promotes the progression of atherosclerosis. Lp(a) has a propensity to remain in the arterial intima and to deposit its load of choleste¬rol and oxidized phospholipids at the sites of plaque formation. Lp(a) is characterized by a dramatically wide range of plasma concentrations (from 0.01 to > 3g/L, or from 2.5nmol/L to > 750nmol/L) that are mainly influenced by genetic factors and not by age, gender or lifestyle. The increase in its circulating concen¬tration is related to the increase in atherothrombotic risk. In this context, Lp(a) assays, although currently insufficiently standardized, are of considerable interest not only for cardiovascular risk strati¬fication in high-risk subjects, but also for the clinical follow-up of patients treated with new lipid-lowering therapies likely to signifi¬cantly reduce its circulating concentration, PCSK9 inhibitors, an¬ti-apo(a) antisense oligonucleotide «ONAS» and, ultimately, to improve the management of subjects at high cardiovascular risk.
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February 2022

Lipoprotein(a): Pathophysiology, measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d'Athérosclérose (NSFA).

Arch Cardiovasc Dis 2021 Dec 25;114(12):828-847. Epub 2021 Nov 25.

Université de Paris, INSERM, Innovative Therapies in Haemostasis, 75006 Paris, France. Electronic address:

Lipoprotein(a) is an apolipoprotein B100-containing low-density lipoprotein-like particle that is rich in cholesterol, and is associated with a second major protein, apolipoprotein(a). Apolipoprotein(a) possesses structural similarity to plasminogen but lacks fibrinolytic activity. As a consequence of its composite structure, lipoprotein(a) may: (1) elicit a prothrombotic/antifibrinolytic action favouring clot stability; and (2) enhance atherosclerosis progression via its propensity for retention in the arterial intima, with deposition of its cholesterol load at sites of plaque formation. Equally, lipoprotein(a) may induce inflammation and calcification in the aortic leaflet valve interstitium, leading to calcific aortic valve stenosis. Experimental, epidemiological and genetic evidence support the contention that elevated concentrations of lipoprotein(a) are causally related to atherothrombotic risk and equally to calcific aortic valve stenosis. The plasma concentration of lipoprotein(a) is principally determined by genetic factors, is not influenced by dietary habits, remains essentially constant over the lifetime of a given individual and is the most powerful variable for prediction of lipoprotein(a)-associated cardiovascular risk. However, major interindividual variations (up to 1000-fold) are characteristic of lipoprotein(a) concentrations. In this context, lipoprotein(a) assays, although currently insufficiently standardized, are of considerable interest, not only in stratifying cardiovascular risk, but equally in the clinical follow-up of patients treated with novel lipid-lowering therapies targeted at lipoprotein(a) (e.g. antiapolipoprotein(a) antisense oligonucleotides and small interfering ribonucleic acids) that markedly reduce circulating lipoprotein(a) concentrations. We recommend that lipoprotein(a) be measured once in subjects at high cardiovascular risk with premature coronary heart disease, in familial hypercholesterolaemia, in those with a family history of coronary heart disease and in those with recurrent coronary heart disease despite lipid-lowering treatment. Because of its clinical relevance, the cost of lipoprotein(a) testing should be covered by social security and health authorities.
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http://dx.doi.org/10.1016/j.acvd.2021.10.009DOI Listing
December 2021

CD160 Expression in Retinal Vessels Is Associated With Retinal Neovascular Diseases.

Invest Ophthalmol Vis Sci 2018 06;59(7):2679-2686

Department of Ophthalmology, Hôpital Robert Debré, Reims, France.

Purpose: Anti-angiogenic agents stand first in the treatment of neovascular diseases of the retina. CD160 appeared in several experimental studies as a marker of activated endothelial cells, suggesting it could represent a promising target for novel anti-angiogenic therapies. The aim of the present study was to assess the distribution of CD160 in the human eye, and to search for a possible correlation with retinal neovascular diseases.

Methods: The physiological distribution of CD160 in the normal eye was assessed with immunolabeling in 10 human donor eyes. Then, in a retrospective cohort of 75 surgical retinal specimens, the density of CD160+ microvessels was evaluated, along with immunolabeling on serial sections against ERG (pan-endothelial cell marker), CD105 (activated endothelial cell marker), and α-SMA (pericyte cell marker). The cohort was divided into two groups: 29 patients with neovascular disease (NV+) and 46 control patients (NV-).

Results: CD160 was physiologically expressed by several cell types: endothelial cells of retinal blood vessels, ganglion cells, macrophages, epithelial cells of the conjunctiva, ciliary body, and retinal pigment epithelium. In the patient cohort, the percentage of CD160+ vessels in the retina was significantly and independently higher in patients suffering from neovascular diseases (P = 0.04). On the contrary, the expression of CD105 was correlated neither with retinal neovascular diseases, nor with CD160 expression.

Conclusions: CD160 was expressed in some retinal vessels in both normal and pathologic eyes. CD160 expression by endothelial cells of retinal vessels was correlated with ocular neovascular diseases. CD160 could therefore represent an interesting target for novel anti-angiogenic therapies.
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http://dx.doi.org/10.1167/iovs.18-24021DOI Listing
June 2018

Production of Elastin-Derived Peptides Contributes to the Development of Nonalcoholic Steatohepatitis.

Diabetes 2018 08 25;67(8):1604-1615. Epub 2018 May 25.

UMR CNRS 7369 MEDyC, University of Reims Champagne-Ardenne, Reims, France

Affecting more than 30% of the Western population, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cancer, hypertension, and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin, or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex (ERC) activation on lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e., SREBP1c and ACC), inflammation (i.e., Kupffer cells, IL-1β, and TGF-β), and fibrosis (collagen and elastin expression). These effects are induced by inhibition of the LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on engagement of the ERC. Our data reveal a major role of EDPs in the development of NASH, and they provide new clues for understanding the relationship between NAFLD and vascular aging.
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http://dx.doi.org/10.2337/db17-0490DOI Listing
August 2018

Circadian disturbance and idiopathic central serous chorioretinopathy.

Graefes Arch Clin Exp Ophthalmol 2016 Nov 21;254(11):2175-2181. Epub 2016 May 21.

Service d'Ophtalmologie, Pôle tête et cou, Hôpital Robert Debré, Centre Hospitalo-Universitaire, 51092, Reims, France.

Background: This present retrospective case control study was designed to evaluate circadian disturbance in patients with chronic idiopathic central serous chorioretinopathy (ICSC).

Methods: Between January 1st, 2012, and November 30th, 2014, 29 consecutive patients with chronic ICSC examined in a referral setting were compared with a gender-matched and age-matched control group of 29 patients. A history of pharmacologic medication (including corticosteroid treatment), sleep disturbance, irregular working hours, cardiovascular risk factors, and depressive anxiety disorders was noted.

Results: The median age of the patients was 52, and in the control subjects it was 50. The male-female ratio for both groups was 4.8:1. Patients with chronic ISCS were more likely to be exposed to irregular working hours (p < 0.01, OR 9.3 [2.29-37.6]) and to present with overweight than the control subjects (p = 0.016). No significant differences were found for sleeping disturbances, pharmacological medication, cardiovascular risk factors, or depressive anxiety disorders.

Conclusions: In this preliminary study, the exposition of irregular working hours as a risk factor for chronic ICSC was identified, which had not been previously reported. If further studies confirm these findings, then employment with regular working hours could be recommended for chronic ICSC patients.
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http://dx.doi.org/10.1007/s00417-016-3378-yDOI Listing
November 2016

Impact of sialic acids on the molecular dynamic of bi-antennary and tri-antennary glycans.

Sci Rep 2016 10 19;6:35666. Epub 2016 Oct 19.

Université de Reims Champagne-Ardenne, UMR CNRS 7369, "Matrice Extracellulaire et Dynamique Cellulaire", UFR Sciences Exactes et Naturelles, Chemin des Rouliers, 51100 Reims, France.

Sialic acids (SA) are monosaccharides that can be located at the terminal position of glycan chains on a wide range of proteins. The post-translational modifications, such as N-glycan chains, are fundamental to protein functions. Indeed, the hydrolysis of SA by specific enzymes such as neuraminidases can lead to drastic modifications of protein behavior. However, the relationship between desialylation of N-glycan chains and possible alterations of receptor function remains unexplored. Thus, the aim of the present study is to establish the impact of SA removal from N-glycan chains on their conformational behavior. We therefore undertook an in silico investigation using molecular dynamics to predict the structure of an isolated glycan chain. We performed, for the first time, 3 independent 500 ns simulations on bi-antennary and tri-antennary glycan chains displaying or lacking SA. We show that desialylation alters both the preferential conformation and the flexibility of the glycan chain. This study suggests that the behavior of glycan chains induced by presence or absence of SA may explain the changes in the protein function.
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http://dx.doi.org/10.1038/srep35666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069492PMC
October 2016

[Management of dyslipidemia in adult].

Rev Prat 2016 Sep;66(7):727-41

Fédération d'endocrinologie, hôpital cardiovasculaire Louis-Pradel, groupe hospitalier Est, 69003 Lyon, France.

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September 2016

Evidence that an HMGA1 gene variant associates with type 2 diabetes, body mass index, and high-density lipoprotein cholesterol in a Hispanic-American population.

Metab Syndr Relat Disord 2014 Feb 22;12(1):25-30. Epub 2013 Oct 22.

1 Cardiovascular Research Institute and Department of Physiological Nursing, University of California , San Francisco, California.

Background: High-mobility group AT-hook 1 (HMGA1) is an important regulator of the insulin receptor gene. We have previously shown in three populations of white European ancestry that the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) is associated with type 2 diabetes mellitus (T2DM). The aim of this study was to measure the frequency of this variant and to determine the degree of the association with T2DM and other features of the metabolic syndrome in a replication cohort of Hispanic Americans.

Methods: This was a retrospective cohort study of well-characterized Hispanic-American participants analyzed in the Genomic Resource in Atherosclerosis (GRA) (Cardiovascular Research Institute, University of California, San Francisco). A total of 1144 individuals were studied, 320 of whom had T2DM. We examined associations of the rs146052672 SNP with T2DM, plasma lipids, lipoproteins, and body mass index (BMI).

Results: In this Hispanic-American cohort, the HMGA1 rs146052672 minor allele (C-insertion) frequency (MAF) was 21.4% with a carrier frequency of 37.4%, considerably higher than we previously observed among GRA white Europeans (MAF 3.1%). The prevalence of the IVS5-13insC variant was significantly higher in those with T2DM compared to controls [42.2% vs. 35.5%; odds ratio (OR) 1.44 95% confidence interval (CI) 1.09-1.90, P=0.011). The variant was also associated with BMI (positively, P=0.045) and plasma high-density lipoprotein cholesterol (HDL-C) (negatively, P=0.047).

Conclusions: As we saw previously among white Europeans, a functional HMGA1 variant was associated with T2DM in individuals of Hispanic-American ethnicity and was present at a much higher frequency.
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http://dx.doi.org/10.1089/met.2013.0086DOI Listing
February 2014

Elastin-derived peptides are new regulators of insulin resistance development in mice.

Diabetes 2013 Nov 6;62(11):3807-16. Epub 2013 Aug 6.

Formations de Recherche en Evolution CNRS 3481, Matrice Extracellulaire et Dynamique Cellulaire, Université de Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Reims, France.

Although it has long been established that the extracellular matrix acts as a mechanical support, its degradation products, which mainly accumulate during aging, have also been demonstrated to play an important role in cell physiology and the development of cardiovascular and metabolic diseases. In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. In chow-fed mice, acute or chronic intravenous injections of EDPs induced hyperglycemic effects associated with glucose uptake reduction and IRES in skeletal muscle, liver, and adipose tissue. Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. This interplay was correlated with decreased sialic acid levels on the β-chain of the IR and reduction of IR signaling. In conclusion, this is the first study to demonstrate that EDPs, which mainly accumulate with aging, may be involved in the insidious development of IRES.
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http://dx.doi.org/10.2337/db13-0508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806616PMC
November 2013

A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components.

Sci Rep 2013 ;3:1491

Department of Health Sciences, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy.

The metabolic syndrome (MetS) is a common disorder, where systemic insulin-resistance is associated with increased risk for type 2 diabetes (T2D) and cardiovascular disease. Identifying genetic traits influencing risk and progression of MetS is important. We and others previously reported a functional HMGA1 gene variant, rs146052672, predisposing to T2D. Here we investigated the association of rs146052672 variant with MetS and related components. In a case-control study from Italy and Turkey, increased risk of MetS was seen among carriers of the HMGA1 variant. In the larger Italian cohort, this variant positively correlated with BMI, hyperglycemia and insulin-resistance, and negatively correlated with serum HDL-cholesterol. Association between rs146052672 variant and MetS occurred independently of T2D, indicating that HMGA1 gene defects play a pathogenetic role in MetS and other insulin-resistance-related conditions. Overall, our results indicate that the rs146052672 variant represents an early predictive marker of MetS, as well as a predictive tool for therapy.
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http://dx.doi.org/10.1038/srep01491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603272PMC
April 2014

Functional variants of the HMGA1 gene and type 2 diabetes mellitus.

JAMA 2011 Mar;305(9):903-12

Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro Magna Græcia, Viale Europa, Germaneto Catanzaro, 88100 Italy.

Context: High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM).

Objective: To examine the association of HMGA1 gene variants with type 2 DM.

Design, Settings, And Participants: Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls.

Main Outcome Measures: The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis.

Results: The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA.

Conclusions: Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.
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http://dx.doi.org/10.1001/jama.2011.207DOI Listing
March 2011

An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients.

J Lipid Res 2008 Aug 25;49(8):1846-54. Epub 2008 Apr 25.

Cardiovascular Research Institute, University of California, San Francisco, CA, USA.

Apolipoprotein A-V (apoA-V) is an important regulator of plasma levels of triglyceride (TG) in mice. In humans, APOA5 genetic variation is associated with TG in several populations. In this study, we determined the effects of the p.185Gly>Cys (c.553G>T; rs2075291) polymorphism on plasma TG levels in subjects of Chinese ancestry living in the United States and in a group of non-Chinese Asian ancestry. The frequency of the less common cysteine allele was 4-fold higher (15.1% vs. 3.7%) in Chinese high-TG subjects compared with a low-TG group (Chi-square = 20.2; P < 0.0001), corresponding with a 4.45 times higher risk of hypertriglyceridemia (95% confidence interval, 2.18-9.07; P < 0.001). These results were replicated in the non-Chinese Asians. Heterozygosity was associated, in the high-TG group, with a doubling of TG (P < 0.001), mainly VLDL TG (P = 0.014). All eleven TT homozygotes had severe hypertriglyceridemia, with mean TG of 2,292 +/- 447 mg/dl. Compared with controls, carriers of the T allele had lower postheparin lipoprotein lipase activity but not hepatic lipase activity. In Asian populations, this common polymorphism can lead to profound adverse effects on lipoprotein profiles, with homozygosity accounting for a significant number of cases of severe hypertriglyceridemia. This specific apoA-V variant has a pronounced effect on TG metabolism, the mechanism of which remains to be elucidated.
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http://dx.doi.org/10.1194/jlr.P800011-JLR200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2444008PMC
August 2008

Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment.

J Clin Invest 2005 Oct;115(10):2862-9

Laboratoire de Biochimie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Benite Cedex, France.

While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia.
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http://dx.doi.org/10.1172/JCI24471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1236672PMC
October 2005

Mechanism for the homocysteine-enhanced antifibrinolytic potential of lipoprotein(a) in human plasma.

Thromb Haemost 2005 Jul;94(1):75-81

INSERM U698, CHU Bichat-Claude Bernard, 46 rue Henri Huchard, F-75877-Cdx, Paris 18, France.

Lipoprotein(a) and total plasma homocysteine levels are now established as independent atherothrombogenic risk factors. A distinctive pathophysiological feature of lipoprotein(a) is its antifibrinolytic activity, an effect dependent on plasma concentration and high affinity for fibrin of its small size apo(a) component. A stimulating effect of homocysteine on purified lipoprotein(a) has been proposed. However, little is known about their specific interactions in human plasma. We demonstrate by immunochemical, ligand-binding and plasminogen activation studies, that homocysteine modifies the structure and function of lipoprotein(a) in human plasma; it reduces the apo(a)/apoB disulfide bond causing the appearance of free apo(a) with high affinity for fibrin that inhibits plasminogen binding and plasmin formation (r= -0.995, p =0.002). These effects were evident particularly in plasma samples containing lipoprotein(a) with low affinity for fibrin and more than 22 kringles apo(a) isoforms. In contrast, for plasmas containing high fibrin affinity lipoprotein(a) (less than 22 kringles apo[a] isoforms) no significant change neither in fibrin binding nor in plasmin formation was observed. Furthermore, isolated apo(a) recombinants (10 to 34 kringles) that have been shown to display size-independent high affinity for fibrin were not affected by homocysteine, thus confirming lipoprotein(a) as its main target. These results suggest that the pro-atherogenic role already conferred to lipoprotein(a) by small apo(a) isoforms may be extended to large apo(a) isoforms if released in plasma by homocysteine, as this mechanism reveals their high fibrin affinity. Lipoprotein(a) and homocysteine may therefore constitute, if acting in concert, a new risk factor for athero-thrombotic vascular disease.
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http://dx.doi.org/10.1160/TH04-12-0808DOI Listing
July 2005

Study of apo(a) length polymorphism and lipoprotein(a) concentrations in subjects with single or double apo(a) isoforms.

Clin Chem Lab Med 2003 May;41(5):634-9

Laboratory of Biochemistry, Robert Debré Hospital, CHU of Reims, Reims, France.

Cardiovascular risk is associated with high lipoprotein(a) (Lp(a)) concentrations and low molecular weight apolipoprotein(a) (apo(a)) isoforms. We studied the relationship between these two biological parameters, particularly in subjects expressing two apo(a) isoforms. Plasma Lp(a) was measured by immunonephelometry in 530 unrelated Caucasian patients at high cardiovascular risk, and apo(a) size determined by immunoblotting using a recombinant standard. Two, one, or no apo(a) isoforms were detected in 258, 270, and 2 subjects, respectively. Lp(a) concentrations showed a non-Gaussian distribution, being higher in the 'double band' than in the 'single band' group (median 0.42 vs. 0.11 g/l, p < 0.0005). Apo(a) size distribution was bimodal, with two frequency peaks at 18 kringles (K) and 27 K. Small size apo(a) isoforms were more frequently found in the 'double band' group, where major isoforms were of lower size than minor isoforms (median 20 vs. 27 K). Regression analysis showed that apo(a) gene length accounted for 33% of Lp(a) variation, with a threshold effect at 20 K, no correlation being found over this value. The minor apo(a) isoform did not significantly influence Lp(a) concentration. These data confirm the relationship between apo(a) size and Lp(a) concentration and suggest that the assessment of cardiovascular risk should take into account the threshold effect at 20 K and the absence of influence of the minor apo(a) isoform.
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http://dx.doi.org/10.1515/CCLM.2003.096DOI Listing
May 2003

Lp(a) particles mold fibrin-binding properties of apo(a) in size-dependent manner: a study with different-length recombinant apo(a), native Lp(a), and monoclonal antibody.

Arterioscler Thromb Vasc Biol 2002 Jul;22(7):1232-8

INSERM U460, Faculté de Médecine Xavier Bichat, Paris, France.

Objective: Small-sized apolipoprotein(a) [apo(a)] isoforms with high antifibrinolytic activity are frequently found in cardiovascular diseases, suggesting a role for apo(a) size in atherothrombosis. To test this hypothesis, we sought to characterize the lysine (fibrin)-binding function of isolated apo(a) of variable sizes.

Methods And Results: Recombinant apo(a) [r-apo(a)] preparations consisting of 10 to 34 kringles and a monoclonal antibody that neutralizes the lysine-binding function were produced and used in parallel with lipoprotein(a) [Lp(a)] particles isolated from plasma in fibrin-binding studies. All r-apo(a) preparations displayed similar affinity and specificity for lysine residues on fibrin regardless of size (K(d) 3.6+/-0.3 nmol/L) and inhibited the binding of plasminogen with a similar intensity (IC50 16.8+/-5.4 nmol/L). In contrast, native Lp(a) particles displayed fibrin affinities that were in inverse relationship with the apo(a) kringle number. Thus, a 15-kringle apo(a) separated from Lp(a) and a 34-kringle r-apo(a) displayed an affinity for fibrin that was higher than that in the corresponding particles (K(d) 2.5 versus 10.5 nmol/L and K(d) 3.8 versus 541 nmol/L, respectively). However, fibrin-binding specificity of the r-apo(a) preparations and the Lp(a) particles was efficiently neutralized (IC50 0.07 and 4 nmol/L) by a monoclonal antibody directed against the lysine-binding function of kringle IV-10.

Conclusions: Our data indicate that fibrin binding is an intrinsic property of apo(a) modulated by the composite structure of the Lp(a) particle.
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http://dx.doi.org/10.1161/01.atv.0000021144.87870.c8DOI Listing
July 2002
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