METABOLIC SYNDROME-ASSOCIATED MURINE AORTIC WALL STIFFENING IS ASSOCIATED WITH PREMATURE ELASTIC FIBERS AGING.

Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is 'one of the deadliest diseases in the world. In 2022, 6.7 million T2D patients died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular actors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 months to non-diabetic mice aged 6 months and 20 months. The comparison with the two non-diabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 months present the same characteristics of ECM wear as those observed in mice aged 20 months. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of DT2 patients.

Circadian disturbance and idiopathic central serous chorioretinopathy.

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.

Tobacco smoking and diabetes. A comparative survey among diabetologists and smoking cessation specialists.

AIMS: Because tobacco smoking is a major risk factor of mortality in diabetes and guidelines suggest evaluating smoking behavior among individuals with diabetes and helping smokers quit, we aimed to assess knowledge about the tobacco smoking - diabetes relationship among diabetologists and smoking cessation specialists (SCS). METHODS: An online cross sectional survey was conceived by the Working Group on Smoking and Diabetes, France. The questionnaire was tested by the members of the Working Group and deemed to be completed in less than 5 min. Only questions receiving the highest number of approval ratings were kept for the survey. The questionnaire was sent to all members of the French Language Society of Diabetes (Société Francophone du Diabète, SFD), N = 969 and the French Language Society on Tobacco (Société Francophone de Tabacologie, SFT), N = 307. The mailing lists of members were obtained with the previous agreement of the societies' board. RESULTS: 225 diabetologists and 97 SCS (response rate 23.2% and 31.5%, respectively) completed the questionnaire. Over 90% of the diabetologists reported recording smoking status of their patients. Although diabetologists were aware that smoking increases all-cause mortality of individuals with diabetes, only 29.3% were aware that smoking is a risk factor for type 2 diabetes (76.3% among SCS), for poor glycemic control: 32.9% (86.6% among SCS). Significantly less diabetologists (64%) than SCS (76.3%) were aware of smoking being a risk factor for microangiopathy. More diabetologists considered that smoking cessation is more important than optimizing glycemic control among individuals with type 2 (69.3%) than among those with type 1 diabetes (47.1%). Few diabetologists (11.1%) and SCS (14.4%) reported to be trained for smoking cessation among persons with diabetes. CONCLUSION: Specific knowledge about the negative tobacco smoking - diabetes association seems to be insufficient among French diabetologists. Diabetologists but also other health care professionals should be trained to help individuals with diabetes who smoke to quit smoking.

Sialic acids cleavage induced by elastin-derived peptides impairs the interaction between insulin and its receptor in adipocytes 3T3-L1.

The insulin receptor (IR) plays an important role in insulin signal transduction, the defect of which is believed to be the root cause of type 2 diabetes. In 3T3-L1 adipocytes as in other cell types, the mature IR is a heterotetrameric cell surface glycoprotein composed of two α subunits and two ß subunits. Our objective in our study, is to understand how the desialylation of N-glycan chains, induced by elastin-derived peptides, plays a major role in the function of the IR. Using the 3T3-L1 adipocyte line, we show that removal of the sialic acid from N-glycan chains (N893 and N908), induced by the elastin receptor complex (ERC) and elastin derived-peptides (EDPs), leads to a decrease in the autophosphorylation activity of the insulin receptor. We demonstrate by molecular dynamics approaches that the absence of sialic acids on one of these two sites is sufficient to generate local and general modifications of the structure of the IR. Biochemical approaches highlight a decrease in the interaction between insulin and its receptor when ERC sialidase activity is induced by EDPs. Therefore, desialylation by EDPs is synonymous with a decrease of IR sensitivity in adipocytes and could thus be a potential source of insulin resistance associated with diabetic conditions.

Smoking and Diabetes: Sex and Gender Aspects and Their Effect on Vascular Diseases.

Smoking and diabetes mellitus (DM) have been identified as 2 major cardiovascular risk factors for many years. In the field of cardiovascular diseases, considering sex differences, or gender differences, or both has become an essential element in moving toward equitable and quality health care. We reviewed the effect of sex or gender on the link between smoking and DM. The risk of type 2 DM due to smoking has been established in both sexes at the same level. As is the case in the general population, the prevalence of smoking in those with DM is higher in men than in women, although the decrease in smoking observed in recent years is more pronounced in men than in women. Regarding chronic DM complications, smoking is an independent risk factor for all-cause mortality, as well as macrovascular and microvascular complications, in both sexes. Nevertheless, in type 2 DM, the burden of smoking appears to be greater in women than in men for coronary heart disease morbidity, with women having a 50% greater risk of fatal coronary event. Women are more dependent to nicotine, cumulate psychosocial barriers to quitting smoking, and are more likely to gain weight, which might make it more difficult for them to quit smoking. Smoking cessation advice and treatments should take into account gender differences to improve the success and long-term maintenance of abstinence in people with and without DM. This might include interventions that address emotions and stress in women or designed to reach specific populations of men.

[Lipoprotein (a) :NSFA consensus]. / Lipoprotéine(a) : consensusde la NSFA 2021.

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 «ONAS¼ and, ultimately, to improve the management of subjects at high cardiovascular risk.

LIPOPROTÉINE(a) : CONSENSUS DE LA NSFA 2021 La lipoprotéine (a) ou Lp(a), initialement décrite en 1963 par Kåre Berg, est constituée d'une lipoprotéine de basse densité (LDL) associée à l'apolipoprotéine (a) [apo(a)]. L'apo(a) est structurelle¬ment similaire au plasminogène, mais ne possède pas l'activité fibrinolytique caractéristique de la plasmine formée à partir de celui-ci. En raison de cette structure complexe, les concentrations élevées de Lp(a) peuvent favoriser la progression des plaques d'athérome grâce à son composant LDL, riche en cholestérol et en phospholipides oxydés, et exercer une action antifibrinolytique et prothrombotique grâce à son composant apo(a). La Lp(a) se carac-térise par une gamme spectaculairement large de concentrations plasmatiques (de 0,01 à plus de 3g/L, c'est-à-dire de 2,5 à plus de 750nmol/L), qui sont principalement influencées par des fac¬teurs génétiques et non par l'âge, le sexe ou le mode de vie. L'augmentation de sa concentration circulante est liée à celle du risque athérothrombotique. Dans ce contexte, le dosage de la Lp(a) présente un intérêt considérable non seulement pour la stratification du risque cardiovasculaire chez les sujets à haut risque mais éga¬lement pour le suivi clinique des patients traités par de nouvelles thérapies hypolipémiantes. Ces nouveaux médicaments, inhibiteurs de PCSK9, oligonucléotides antisens ou ONAS anti-apo(a), seraient susceptibles d'en réduire significativement la concentration circu¬lante et, à terme, d'améliorer la prise en charge des sujets à haut risque cardiovasculaire.

Burden of cardiovascular disease in a large contemporary cohort of patients with heterozygous familial hypercholesterolemia.

Background and aims: Heterozygous familial hypercholesterolemia (HeFH) is increasingly better diagnosed and treatments can improve the cardiovascular prognosis. We evaluated the long-term cardiovascular risk of HeFH using the French REgistry of Familial hypERCHOLesterolemia (REFERCHOL). Methods: We studied HeFH patients diagnosed genetically and clinically by the Dutch Lipid Clinic Network (DLCN) criteria in all lipid clinics across the country and their 5-year risk of cardiovascular events (all fatal and non-fatal acute coronary, cerebral and peripheral arterial disease events, aortic valve replacement surgery) using the French national health data system. Results: The database comprised 3202 individuals, 2010 (62.8%) with genetically verified HeFH and 1192 (37.2%) a DLCN score ≥6. Of these individuals, 2485 (77.6%) were in primary prevention and 717 (22.4%) in secondary prevention. The incidence of cardiovascular events was 24.58 per 1000 person-years for the overall sample, 19.15 in primary prevention and 43.40 in secondary prevention. The incidence of myocardial infarction, cerebral infarction and death was 16.32 per 1000 person-years for the overall sample, 12.93 in primary prevention and 28.08 in secondary prevention. The incidence of aortic valve replacement was 1.78 per 1000 person-years. In the overall sample, at inclusion, 41% were not treated for LDL cholesterol, 48% of these in primary prevention and 20% in secondary prevention and high-dose statins were used by only 24% of individuals, 15% of these in primary prevention and 45% in secondary prevention. Conclusions: The incidence of cardiovascular events in HeFH is high and lipid-lowering treatment is far from optimal. The cardiovascular risk of HeFH is underestimated and patients are inadequately treated.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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-1ß, and TGF-ß), 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.

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

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.

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

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.

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.

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.

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

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.

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

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 ß-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.

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

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.