PPAR在动脉粥样硬化发生与发展中的作用

动脉粥样硬化(AS)是一种以动脉壁脂质蓄积为特征的复杂病变过程。过氧化酶体增殖物激活型受体(PPAR)是核内孤儿受体家族成员,它作为脂质和脂蛋白代谢的调节物,可以调控血浆胆固醇及甘油三酯的水平、促进脂肪细胞分化、影响巨噬细胞内胆固醇内稳态、稳定斑块、抑制血小板聚积从而影响AS的发生和发展。PPAR可通过对基因转录的调控来调理脂质代谢紊乱,并在血管壁水平直接产生抗AS作用。     

Both Fasting and Glucose-Stimulated Proinsulin Levels Predict Hyperglycemia and Incident Type 2 Diabetes: A Population-Based Study of 9,396 Finnish Men

Background

Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin.

Methods

Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m²) of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC) and proinsulin to insulin ratios were calculated.

Results

Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index) or insulin secretion (Disposition index) weakened these associations. Insulin sensitivity had a major impact on these associations.

Conclusion

Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes.     

High Fat High Cholesterol Diet (Western Diet) Aggravates Atherosclerosis,Hyperglycemia and Renal Failure in Nephrectomized LDL Receptor Knockout Mice: Role of Intestine Derived Lipopolysaccharide

A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.     

Ambient Air Pollution and the Progression of Atherosclerosis in Adults

Background

Cross-sectional studies suggest an association between exposure to ambient air pollution and atherosclerosis. We investigated the association between outdoor air quality and progression of subclinical atherosclerosis (common carotid artery intima-media thickness, CIMT).

Methodology/Principal Findings

We examined data from five double-blind randomized trials that assessed effects of various treatments on the change in CIMT. The trials were conducted in the Los Angeles area. Spatial models and land-use data were used to estimate the home outdoor mean concentration of particulate matter up to 2.5 micrometer in diameter (PM2.5), and to classify residence by proximity to traffic-related pollution (within 100 m of highways). PM2.5 and traffic proximity were positively associated with CIMT progression. Adjusted coefficients were larger than crude associations, not sensitive to modelling specifications, and statistically significant for highway proximity while of borderline significance for PM2.5 (P = 0.08). Annual CIMT progression among those living within 100 m of a highway was accelerated (5.5 micrometers/yr [95%CI: 0.13–10.79; p = 0.04]) or more than twice the population mean progression. For PM2.5, coefficients were positive as well, reaching statistical significance in the socially disadvantaged; in subjects reporting lipid lowering treatment at baseline; among participants receiving on-trial treatments; and among the pool of four out of the five trials.

Conclusion

Consistent with cross-sectional findings and animal studies, this is the first study to report an association between exposure to air pollution and the progression of atherosclerosis – indicated with CIMT change – in humans. Ostensibly, our results suggest that air pollution may contribute to the acceleration of cardiovascular disease development – the main causes of morbidity and mortality in many countries. However, the heterogeneity of the volunteering populations across the five trials, the limited sample size within trials and other relevant subgroups, and the fact that some key findings reached statistical significance in subgroups rather than the sample precludes generalizations to the general population.     

2型糖尿病患者血清LDL，CysC与动脉粥样硬化的相关性研究

目的:分析2型糖尿病(T2DM)患者血清低密度脂蛋白(LDL)、胱抑素C(CysC)与动脉粥样硬化(AS)的相关性。方法:选取2型糖尿病患者300名,根据颈动脉内膜中膜厚度分为非动脉粥样硬化斑块组(n=109)和动脉粥样硬化斑块组(n=191),并对动脉粥样硬化斑块的相关危险因素进行多因素Logistic回归分析。结果:(1)Pearson相关分析显示,LDL、CysC水平与IMT值呈正相关(P0.05)。(2)单因素分析示,非AS组和AS组两组间LDL(t=8.876,P0.05)、CysC(t=7.985,P0.05)、HbA1c(t=9.912,P0.05)、Hs-CRP(t=12.461,P0.05)、年龄(t=7.114,P0.05)、UA((t=8.618,P0.05)间差异有统计学意义;(3)多因素Logistic回归分析示,LDL、CysC、HbA1c、年龄是T2DM并AS的独立危险因素(P0.05);结论:LDL与CysC水平是T2DM并AS的独立危险因素。     

Association of Small Dense LDL Serum Levels and Circulating Monocyte Subsets in Stable Coronary Artery Disease

Objective

Atherosclerosis is considered to be an inflammatory disease in which monocytes and monocyte-derived macrophages play a key role. Circulating monocytes can be divided into three distinct subtypes, namely in classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+) and non-classical monocytes (NCM; CD14+CD16++). Low density lipoprotein particles are heterogeneous in size and density, with small, dense LDL (sdLDL) crucially implicated in atherogenesis. The aim of this study was to examine whether monocyte subsets are associated with sdLDL serum levels.

Methods

We included 90 patients with angiographically documented stable coronary artery disease and determined monocyte subtypes by flow cytometry. sdLDL was measured by an electrophoresis method on polyacrylamide gel.

Results

Patients with sdLDL levels in the highest tertile (sdLDL≥4mg/dL;T3) showed the highest levels of pro-inflammatory NCM (15.2±7% vs. 11.4±6% and 10.9±4%, respectively; p<0.01) when compared with patients in the middle (sdLDL=2-3mg/dL;T2) and lowest tertile (sdLDL=0-1mg/dL;T1). Furthermore, patients in the highest sdLDL tertile showed lower CM levels than patients in the middle and lowest tertile (79.2±8% vs. 83.9±7% and 82.7±5%; p<0.01 for T3 vs. T2+T1). Levels of IM were not related to sdLDL levels (5.6±4% vs. 4.6±3% vs. 6.4±3% for T3, T2 and T1, respectively). In contrast to monocyte subset distribution, levels of circulating pro- and anti-inflammatory markers were not associated with sdLDL levels.

Conclusion

The atherogenic lipoprotein fraction sdLDL is associated with an increase of NCM and a decrease of CM. This could be a new link between lipid metabolism dysregulation, innate immunity and atherosclerosis.     

Effects of Total Hypophysectomy on the Glycemic and Plasma Cholesterol Levels in the Snake,Natrix piscator (Russell)

The changes in the levels of blood sugar and plasma cholesterol and the histology of the pancreatic islets were studied following hypophysectomy in the snake, Natrix piscator. Hypophysectomy in N. piscator produced a progressive decrease in glycemia and after 15 days, an aglycemic condition developed accompanied by slight degranulatory changes in the alpha cells of the pancreatic islet tissue. A significant decrease in the muscle glycogen concentration was also noticed 15 days after the operation. Atrophic changes were evident in the thyroid and adrenal glands of the operated animals. An extract of three pituitaries when injected in a normal snake did not produce any change in the blood sugar level. It is suggested that the absence of a diabetogenic action following injection of pituitary extract may be due to the opposing action of the endogenously produced insulin in the intact pancreas of the animal.     

中、重度牙周炎与冠心病患者白细胞介素17 及血脂水平的比较

目的:研究汉族人群中、重度牙周炎与冠心病的相关性并初步探讨白细胞介素17在二者相关性中的可能作用。方法:检测和分析40名健康者(健康组)、40例中、重度牙周炎患者(牙周炎组)、28例冠状动脉粥样硬化性心脏病患者(冠心病组)及47例患冠心病伴中、重度牙周炎的患者(冠心病+牙周炎组)血清白细胞介素17水平、血脂水平(血清低密度脂蛋白、高密度脂蛋白、胆固醇、总胆固醇和甘油三酯)和牙周临床指数(附着丧失、探诊深度和探诊出血)。结果:单因素方差分析结果显示,健康组、牙周炎组、冠心病组及牙周炎+冠心病组的血清白细胞介素17水平分别为(13.01±1.23)、(24.45±2.13)、(59.90±2.23)和(68.87±3.43)ng/L,各组血清白细胞介素17间的差异具有统计学意义(P<0.05),且经协方差分析校正年龄、受教育状况、血压和体重指数后显示,各组血清白细胞介素17水平间的差异仍具有统计学意义(P<0.05)。多元Logistic回归分析结果显示,中、重度牙周炎患者发生冠心病的可能性高于牙周健康者,其发生冠心病的相对风险率比值比为2.416(P=0.039;95%CI:1.126-6.659)。经协方差分析校正年龄、受教育状况、血压和体重指数后,各组血清总胆固醇水平间差异仍具有统计学意义(P=0.018)。结论:严重的牙周感染可能通过改变白细胞介素17水平,影响全身炎症反应和冠心病的发生及发展,可能是冠心病事件的危险因素之一。     

Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression

Background

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1^−/− mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1^−/− mice receiving only 2-hydroxypropyl-β-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit.

Methodology/Principal Findings

Administration of CD to Npc1^−/− mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2^−/− mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage.

Conclusions/Significance

Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1^−/− and Npc2^−/− mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.     

Pericardial Fat and Atrial Conduction Abnormalities in the Multiethnic Study of Atherosclerosis (MESA)

Pericardial fat (Pfat) overlies the cardiac surface including atria and their inter‐ and intra‐conduction system. Through its local inflammatory effects, Pfat may predispose to atrial abnormalities that could be detected as changes in P‐wave morphology in the 12‐lead electrocardiogram (ECG). We evaluated the association between Pfat and ECG measurements of P wave and PR interval (referred to as P‐wave indexes): PR duration (PR‐dur), P‐wave duration (P‐dur), and P‐wave terminal force (P‐term), in the Multiethnic Study of Atherosclerosis (MESA). Participants with available Pfat measured by computed tomography (CT) and P‐wave indexes measured by ECG were included (N = 996). Differences in P‐wave indexes per 1 standard deviation difference in Pfat were tested in unadjusted linear regression analysis first, then adjusted for demographics (age, sex, and ethnicity), and further adjusted for measures of adiposity (BMI or waist circumference (WC)), or cardiovascular risk factors (hypertension (HTN), diabetes, and smoking). All P‐wave indexes were significantly associated with Pfat in unadjusted analyses (regression‐coefficient (β) (95% CI): PR‐dur (ms) 2.53 (1.02, 4.04), P‐dur (ms) 2.59 (1.84, 3.35), P‐term (µV·s) 0.25 (0.13, 0.36)). After demographics adjustment, P‐dur (1.68 (0.87, 2.49)) and P‐term (0.16 (0.04,0.28)), but not PR‐dur (1.11 (?0.52, 2.74)) were associated with Pfat. No associations were significant after adjustment for BMI, WC, or cardiovascular disease (CVD) risk factors. BMI and WC, separately, were significantly associated with P‐wave indexes in all models, including those that included Pfat as a covariate. BMI, but not WC, was associated with P‐wave indexes when the two were entered into the same model. In conclusion, Pfat is associated with P‐wave indexes, but not after adjusting for measures of adiposity or CVD risk factors. Among Pfat, BMI and WC, BMI had the most robust association with P‐wave indexes. These findings raise doubts about potential local effects of Pfat on atrial electrophysiology and morphology     

Enterostatin (VPDPR) and Its Peptide Fragment DPR Reduce Serum Cholesterol Levels after Oral Administration in Mice

We found that enterostatin (VPDPR), an anorexigenic peptide for a high-fat diet, significantly reduces serum cholesterol levels after oral administration of 100 mg/kg for 3 days in mice fed a high cholesterol-cholic acid diet. DPR, a peptide fragment of VPDPR, also had hypocholesterolemic activity at a dose of 50 mg/kg. Food intake was not suppressed under these dietary conditions. Fecal excretion of cholesterol and bile acids was increased significantly by both VPDPR and DPR. Interestingly, DPR induced hypocholesterolemic effects just two hours after a single oral administration at a dose of 100 mg/kg.     

Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis

Introduction

In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.

Methods

Incidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated.

Results

The incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59±7 vs. 55±6 years old, p=0.03), had higher triglyceride levels (137±86 vs. 97±60 mg/dL, p=0.03), and higher systolic blood pressure (129±17 vs. 117±15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p<=0.05). RA patients with any CAC at baseline had a median rate of yearly progression of 21 (7–62) compared to 21 (5–70) Agatston units in controls. No statistical differences between RA progressors and RA non-progressors were observed for inflammatory markers or for RA disease characteristics.

Conclusions

The incidence and progression of CAC did not differ between RA and non-RA participants. In patients with RA, incident CAC was associated with older age, higher triglyceride levels, and higher blood pressure, but not with inflammatory markers or RA disease characteristics.     

Association of Sick Sinus Syndrome with Incident Cardiovascular Disease and Mortality: The Atherosclerosis Risk in Communities Study and Cardiovascular Health Study

Background

Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.

Methods

We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.

Results

During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14–1.70), coronary heart disease (HR 1.72, 95%CI 1.11–2.66), heart failure (HR 2.87, 95%CI 2.17–3.80), stroke (HR 1.56, 95%CI 0.99–2.46), AF (HR 5.75, 95%CI 4.43–7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9–67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51–2.66), AF (HR 4.25, 95%CI 3.28–5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8–32.1).

Conclusion

Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.     

Dispersion of Small Ceramic Particles (Al(2)O(3)) with Azotobacter vinelandii

The high surface charge of small ceramic particles such as alumina particles prevents them from dispersing evenly in aqueous suspensions and forming high-density compacts. However, suspensions of 400-nm-diameter alumina particles treated with alginate from the bacterium Azotobacter vinelandii were well dispersed. The alginate bound firmly to the particle surface and could not be removed by repeated washing with distilled water (2.82 mg of the bacterial alginate adsorbed to 1 g of the alumina particles). Furthermore, A. vinelandii grew and produced alginate in the presence of up to 15% (vol/vol) alumina particles. These results suggest that an in situ process using this bacterium to coat ceramic particles with alginate might be developed. In in situ processing experiments, the particle-packing densities were significantly increased and the viscosities of 5 and 10% (vol/vol) suspensions were reduced 4- and 60-fold, respectively, over those of controls. The bacteria were readily removed from the alumina particles by washing.     

Dispersion of Small Ceramic Particles (Al2O3) with Azotobacter vinelandii

The high surface charge of small ceramic particles such as alumina particles prevents them from dispersing evenly in aqueous suspensions and forming high-density compacts. However, suspensions of 400-nm-diameter alumina particles treated with alginate from the bacterium Azotobacter vinelandii were well dispersed. The alginate bound firmly to the particle surface and could not be removed by repeated washing with distilled water (2.82 mg of the bacterial alginate adsorbed to 1 g of the alumina particles). Furthermore, A. vinelandii grew and produced alginate in the presence of up to 15% (vol/vol) alumina particles. These results suggest that an in situ process using this bacterium to coat ceramic particles with alginate might be developed. In in situ processing experiments, the particle-packing densities were significantly increased and the viscosities of 5 and 10% (vol/vol) suspensions were reduced 4- and 60-fold, respectively, over those of controls. The bacteria were readily removed from the alumina particles by washing.     

Statistical Modeling of Agatston Score in Multi-Ethnic Study of Atherosclerosis (MESA)

The MESA (Multi-Ethnic Study of Atherosclerosis) is an ongoing study of the prevalence, risk factors, and progression of subclinical cardiovascular disease in a multi-ethnic cohort. It provides a valuable opportunity to examine the development and progression of CAC (coronary artery calcium), which is an important risk factor for the development of coronary heart disease. In MESA, about half of the CAC scores are zero and the rest are continuously distributed. Such data has been referred to as “zero-inflated data” and may be described using two-part models. Existing two-part model studies have limitations in that they usually consider parametric models only, make the assumption of known forms of the covariate effects, and focus only on the estimation property of the models. In this article, we investigate statistical modeling of CAC in MESA. Building on existing studies, we focus on two-part models. We investigate both parametric and semiparametric, and both proportional and nonproportional models. For various models, we study their estimation as well as prediction properties. We show that, to fully describe the relationship between covariates and CAC development, the semiparametric model with nonproportional covariate effects is needed. In contrast, for the purpose of prediction, the parametric model with proportional covariate effects is sufficient. This study provides a statistical basis for describing the behaviors of CAC and insights into its biological mechanisms.     

Novel Association between Plasma Matrix Metalloproteinase-9 and Risk of Incident Atrial Fibrillation in a Case-Cohort Study: The Atherosclerosis Risk in Communities Study

Background

Previous cross-sectional studies have suggested that biomarkers of extracellular matrix remodelling are associated with atrial fibrillation (AF), but no prospective data have yet been published. Hence, we examine whether plasma matrix metalloproteinases (MMP) and their inhibitors are related to increased risk of incident AF.

Methods

We used a case-cohort design in the context of the prospective Atherosclerosis Risk in Communities (ARIC) study. From 13718 eligible men and women free from AF in 1990-92, we selected a stratified random sample of 500 individuals without and 580 with incident AF over a mean follow-up of 11.8 years. Using a weighted proportional hazards regression model, the relationships between MMP-1, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2 and C-terminal propeptide of collagen type-I with incident AF were examined after adjusting for confounders.

Results

In models adjusted for age, sex and race, all biomarkers were associated with AF, but only the relationship between plasma MMP-9 remained significant in the fully-adjusted model: each one standard deviation increase in MMP-9 was associated with 27% (95% Confidence Interval: 7% to 50%) increase in risk of AF with no evidence of an interaction with race or sex. Individuals with above mean levels of MMP-9 were more likely to be male, white and current smokers.

Conclusions

The findings suggest that elevated levels of MMP-9 are independently associated with increased risk of AF. However, given the lack of specificity of MMP-9 to atrial tissue, it remains to be determined whether the observed relationship reflects the impact of atrial fibrosis or more generalized fibrosis on risk of incident AF.