Molecular study of human herpesvirus 6 and 8 involvement in coronary atherosclerosis and coronary instability

Several lines of evidence suggest the involvement of infectious agents in the pathogenesis of atherosclerosis. Furthermore, a correlation between infection‐driven inflammatory burden and acute manifestation of coronary artery disease has been hypothesized. The aim of this work was to assess whether human herpesvirus (HHV)‐6 and HHV‐8, two DNA viruses with a distinct tropism for endothelium and lymphocytes, may be associated with coronary instability. An age‐ and gender‐matched cross‐sectional study was undertaken in 70 patients with testing of plasma HHV‐6 and HHV‐8 DNA load in different cardiovascular clinical settings: 29 patients with acute myocardial infarction, 21 patients with stable coronary artery disease, and 20 patients without coronary and carotid artery atherosclerosis subjected to cardiac valve replacement. In all patients, HHV‐6 and HHV‐8 plasma DNA was tested by using highly sensitive, calibrated quantitative real‐time PCR assays which employ a synthetic DNA calibrator to adjust for DNA extraction and amplification efficiency. HHV‐8 viremia was undetectable in all three groups. HHV‐6 viremia was detected in a substantial fraction of the samples examined (18.6%) without significant differences among the three groups (ST segment elevation myocardial infarction: 17.2%; stable coronary artery disease: 14.3%; patients without coronary and carotid artery atherosclerosis: 25%). Furthermore, no significant differences in plasma HHV‐6 load were observed amongst the three groups of patients. These findings indicate that coronary instability is not associated specifically with active HHV‐6 or HHV‐8 infection. However, an unusually high rate of active HHV‐6 infection was documented among patients without atherosclerosis admitted to hospital with cardiac disease. J. Med. Virol. 84:1961–1966, 2012. © 2012 Wiley Periodicals, Inc.     

The role of high-sensitivity C-reactive Protein,interleukin-6 and cystatin C in ischemic stroke complicating atrial fibrillation

This study examined the role of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and cystatin C in ischemic stroke complicating atrial fibrillation (AF) and the relationship of systemic inflammation with this disease in order to identify AF patients who are at high risk of stroke and need optimal anticoagulant therapy.A total of 103 AF patients, simple (n=75) or complicated by ischemic stroke (n=28), and 112 control subjects were recruited.IL-6 level was detected by using enzyme linked immunosorbent assay.Cystatin C and hsCRP levels were measured by means of a particle-enhanced immunonephelometric assay.The results showed that the AF patients had higher levels of hsCRP (P=0.004), IL-6 (P=0.000), and cystatin C (P=0.000) than control subjects.Plasma hsCRP level was increased in the AF patients with ischemic stroke as compared to the patients with simple AF (P=0.036).The AF patients who had the level of hsCRP exceeding 3.83 mg/L were at a higher risk than those with hsCRP level lower than 3.83 mg/L (P=0.030).After adjusting for other factors, cystatin C remained positively associated with IL-6 (r=0.613) and hsCRP (r=0.488).It was concluded that hsCRP is positively correlated with ischemic stroke complicating AF and may be a risk factor independent of other risk factors for AF.Elevated cystatin C level is also indicative of the increased risk of AF.     

脂肪酸诱导脂肪细胞促酰化蛋白抵抗及机制研究

目的:观察不同浓度单不饱和脂肪酸(油酸)和饱和脂肪酸(棕榈酸)对3T3-L1(前)脂肪细胞葡萄糖转运的影响,探讨高游离脂肪酸(FFA)负荷在促酰化蛋白(ASP)抵抗形成中的意义,及FFA诱导的3T3-L1(前)脂肪细胞ASP抵抗的机制。方法:体外培养3T3-L1细胞,诱导细胞分化,用不同浓度FFA作用于3T3-L1(前)脂肪细胞,孵育过夜后收获细胞,采用2-脱氧-[3H]-D-葡萄糖掺入法,观察3T3-L1成熟脂肪细胞和前脂肪细胞基础状态和ASP刺激状态的葡萄糖摄取率;采用Western blotting法检测基础状态和ASP刺激的鸟苷酸结合蛋白alpha-q/11(Gαq/11),鸟苷酸结合蛋白beta(Gβ),磷酸化蛋白激酶Calpha(p-PKCα)和磷酸化蛋白激酶Czeta(p-PKCζ)蛋白表达。结果:ASP刺激后,3T3-L1成熟脂肪细胞和前脂肪细胞葡萄糖摄取率分别是基础状态的1.98倍(P0.01)和2.87倍(P0.01)。低浓度FFA不影响ASP刺激的葡萄糖转运;而1.0mmol/L时油酸组和棕榈酸组ASP刺激的成熟脂肪细胞葡萄糖摄取率分别减少47%(P0.05)和34%(P0.05),前脂肪细胞葡萄糖摄取率分别减少43%(P0.05)和62%(P0.01)。1.0mmol/L油酸和棕榈酸抑制成熟脂肪细胞基础状态和ASP刺激的Gβ、Gαq/11、p-PKCα和p-PKCζ蛋白表达,油酸组ASP刺激的蛋白表达分别减少了47%Gβ(P0.01),44%Gαq/11(P0.05)、39%p-PKCα(P0.05)和20%p-PKCζ(P0.05);棕榈酸组也可观察到类似现象(P0.05或P0.01)。在前脂肪细胞,油酸仅抑制ASP刺激的p-PKCα和p-PKCζ(均P0.05)蛋白表达;而棕榈酸下调上述4种信号蛋白的表达(P0.05或P0.01)。结论:油酸或棕榈酸抑制3T3-L1成熟脂肪细胞和前脂肪细胞ASP刺激的葡萄糖转运,证明FFA诱导脂肪细胞产生胰岛素抵抗状态下同时存在ASP抵抗。FFA诱导的ASP抵抗的发生机制与其干扰ASP-C5L2信号转导途径有关。ASP抵抗参与了"脂毒性"-胰岛素抵抗/肥胖症的病理生理过程。     

Protease inhibitor effects on triglyceride synthesis and adipokine secretion in human omental and subcutaneous adipose tissue

OBJECTIVE: Significant advances in the treatment of the morbidity and mortality associated with AIDS are also associated with undesirable side-effects in fat redistribution (lipodystrophy), insulin resistance and cardiovascular risk, which is directly linked to protease inhibitor (PI) treatment. METHODS: The effects of four different PIs on triglyceride (TG) storage and adipokine production (leptin, adiponectin, and acylation stimulating protein [ASP]) in omental (OM) and subcutaneous (SC) adipose tissues were examined. RESULTS: Initial results demonstrated that saquinivir (SQV) and ritonivir (RTV) had little observed effect on de novo TG synthesis ([3H]glucose incorporation into TG) or fatty acid re-esterification ([14C]oleate incorporation into TG), whereas amprenivir (APV) and indinivir (IDV) reduced TG synthesis, especially in SC tissue up to 30+/-5.8% P<0.05 and 46+/-7.8% P<0.001, at 20 microM, respectively. There was no observed effect on phospholipid synthesis, tissue protein or toxicity. Only APV and IDV decreased leptin and adiponectin secretion in SC tissue, in a time- and concentration-dependent manner: at 18 h, leptin was inhibited by 54+/-3.1% (P<0.001) and 44+/-6.4% (P<0.001) by APV and IDV (40 microM), respectively, and adiponectin was inhibited by 35+/-5.6%(P<0.001) and 25+/-12.3% (P<0.05) by APV and IDV (40 IuM), respectively. By contrast, both IDV and APV decreased ASP secretion in OM tissues by a maximum of 53 +/-7.8% (P<0.001) and 59+/-5.9% (P<0.001), respectively, and by a maximum of 86+/-1.6% (P<0.001) and 72 +/-4% (P<0.001), respectively, in SC tissues. CONCLUSION: PI have a direct effect on human adipose tissue which are site, PI and adipokine specific; these effects may contribute to the overall adipose imbalance and development of lipodystrophy, and metabolic syndrome in HIV-positive individuals.     

New insights into molecular mechanisms of diffuse coronary ectasiae: a possible role for VEGF

BACKGROUND: Diffuse coronary artery ectasiae (DCE) are occasionally found at necropsy or at angiography. Pathogenetic mechanisms of DCE are still poorly known. Matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and vascular endothelial growth factor (VEGF) are involved in vascular remodeling and may play a role in DCE. METHODS: A total of 1280 consecutive coronary angiograms performed in a single institution in 1 year were screened. DCE were found in 15 patients. Diagnosis at hospital admission was acute coronary syndromes in all of them. Two patients died during initial admission and 1 refused blood sampling; the remaining 12 patients were enrolled in the study. No patient with DCE exhibited coronary stenoses. Plasma levels of VEGF, MMP-2, TIMP-1, TIMP-2 and C-reactive protein (CRP) were measured in these 12 patients 12 months after discharge during a silent clinical phase, in 12 age- and sex-matched patients with stable angina (SA) and coronary artery disease, and in 12 age- and sex-matched patients with normal coronary arteries (NCA). RESULTS: VEGF levels were higher in patients with DCE than in SA or NCA (151.6 pg/ml [36.2-252.9] vs. 66.6 pg/ml [36.4-93.3] and 54.8 pg/ml [14.5-87.1], respectively, p = 0.012]. TIMP-2 levels were lower in DCE and SA than in NCA (5.9 ng/ml [0-33.6] and 5.0 [0-17.4] vs. 139.3 ng/ml [114.4-237.4], respectively, p < 0.001). TIMP-1 and MMP-2 plasma levels were similar in all groups (p = NS), and CRP levels were within normal limits (< 3 mg/L) in most patients, irrespective of their coronary anatomy (75% for DCE, 66% for SA, and 84% for NCA [p = NS]). CONCLUSIONS: Symptomatic patients with DCE typically present with an acute coronary syndrome and exhibit lack of obstructive stenosis at angiography, decreased plasma levels of TIMP-2 and raised plasma levels of VEGF. The simultaneous occurrence of reduced MMPs inhibition and increased angiogenetic activity suggests an accelerated and persistent extracellular matrix remodeling process favouring arterial remodeling and aneurysms formation which is likely to enhance the risk of thrombosis because of low shear stress.     

Visfatin concentration in Asian Indians is correlated with high density lipoprotein cholesterol and apolipoprotein A1

BACKGROUND: Visfatin is a recently described adipose tissue derived hormone whose role in humans remains largely unknown. OBJECTIVES: To determine visfatin's relationship to lipoproteins and body composition parameters in Asian Indians and Caucasians. DESIGN: A cross-sectional study. PATIENTS: Men and women living in Montreal, Canada between the ages of 20 and 60 years were recruited for participation in this study. Subjects were excluded if they had a history of CVD or were taking lipid lowering medication. Individuals identified themselves as Asian Indian or Caucasian. MEASUREMENTS: Anthropometric measurements were collected including weight, height, waist circumference, hip circumference and body fat percentage (BF%). Serum samples were analysed for total cholesterol, HDL-C, apoA1, apoB and visfatin. RESULTS: There was no difference in visfatin levels between Indian and Caucasian men (64.50 +/- 3.98 ng/ml vs 73.01 +/- 6.45 ng/ml, ns, respectively) and Indian and Caucasian women (59.03 +/- 5.71 ng/ml vs 77.70 +/- 7.63 ng/ml, ns, respectively), despite large differences in BF%, apoB and the apoB/apoA1 ratio. Visfatin correlated positively to HDL-C and apoA1 in the Indian men (R = 0.42, P = 0.004 and R = 0.48, P = 0.003) and Indian women (R = 0.46, P = 0.05 and R = 0.59, P = 0.01). CONCLUSION: Visfatin concentrations may be related to HDL metabolism in Asian Indian immigrants.