BACKGROUND & AIMS: :We evaluated the differences in strength of the associations of prevalent cardiovascular disease and lower extremity arterial atherosclerosis to common carotid intima-media thickness, assessed by near wall measurements only, by far wall measurements only, and by the average of near and far wall measurements. The study was based on data from 1500 participants of the Rotterdam Study, a single-center-population-based prospective follow-up study among 7983 subjects, aged 55 years or over. Comparison of the strength of the associations of near wall intima-media thickness and of combined near and far wall intima-media thickness to cardiovascular disease and lower extremity arterial atherosclerosis revealed significantly stronger associations compared to associations observed for far wall intima-media thickness, in particular for stroke and lower extremity arterial disease. We conclude that near wall common carotid intima-media thickness measurement provides at least as good an indicator of atherosclerosis elsewhere and of cardiovascular risk as the far wall intima-media thickness measurement.

背景与目标： : 我们评估了流行的心血管疾病和下肢动脉粥样硬化与颈总动脉内膜中层厚度的相关性的强度差异，仅通过近壁测量，仅通过远壁测量以及近壁和远壁测量的平均值来评估。该研究基于鹿特丹研究的1500名参与者的数据，该研究是一项基于单中心人群的前瞻性随访研究，涉及7983名年龄在55岁或以上的受试者。比较近壁内膜-中膜厚度以及近壁和远壁内膜-中膜厚度与心血管疾病和下肢动脉粥样硬化的相关性，发现与观察到的远壁内膜-中膜厚度的相关性相比，相关性明显更强，特别是对于中风和下肢动脉疾病。我们得出的结论是，近壁颈总动脉内膜中层厚度的测量至少与远壁内膜中层厚度的测量一样，可以很好地指示其他地方的动脉粥样硬化和心血管风险。

BACKGROUND & AIMS: BACKGROUND:We sought to investigate the effects of lin-/sca+ cells, endothelial progenitor cells (EPCs) and granulocyte colony-stimulating factor (G-CSF) administration on atherosclerotic plaque progression. METHODS:Apolipoprotein E-deficient (apoE(-/-)) mice were splenectomized and treated with high-cholesterol diet for 6 weeks in order to induce atherosclerotic plaque development. Bone marrow-derived Lin-/sca-1+ cells were isolated and further cultured to early growth endothelial progenitor cells (EPCs). Mice were divided in four groups (n=10/group) and received two intravenous injections of 5×10(5) cells (lin-/sca-1+ or EPCs), or granulocyte colony-stimulating factor (G-CSF 100 μg/kg/day) for 7 days or normal saline. The same interventions were administered to animals, which had undergone unilateral hind-limb ischemia. Effects on inflammatory parameters, lesion severity, and atherosclerotic plaque area size were assessed. RESULTS:The administration of both G-CSF and progenitor cells significantly decreased the levels of IL-6, 6 weeks after the initiation of treatment. Atherosclerotic lesion area was reduced by G-CSF (atherosclerotic plaque area percentage 22.94%±3.68, p=0.001), by lin-/sca-1+ (23.27%±5.98, p=0.002) and cultured EPCs (23.16±4.86%, p=0.002) compared to control (32.75%±7.05). In the atherosclerotic mice that underwent limb ischemia, the atherosclerotic plaque area, was not significantly different between the treatment groups cultured EPCs-treated mice and the control group (p=NS, for all). CONCLUSIONS:Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells decreased plaque progression and levels of inflammatory molecules in a murine model of atherosclerosis. Treatment with G-CSF, lin-/sca-1+, or EPCs may exert beneficial effects on vascular inflammation and atherosclerotic plaque progression. However, the effects are diminished in an ischemic setting.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Type 2 diabetes increases the risk of coronary heart disease (CHD), yet the mechanisms involved remain poorly described. Polygenic risk scores (PRS) provide an opportunity to understand risk factors since they reflect etiologic pathways from the entire genome. We therefore tested whether a PRS for CHD influenced risk of CHD in individuals with type 2 diabetes and which risk factors were associated with this PRS. METHODS:We tested the association of a CHD PRS with CHD and its traditional clinical risk factors amongst individuals with type 2 diabetes in UK Biobank (N = 21,102). We next tested the association of the CHD PRS with atherosclerotic burden in a cohort of 352 genome-wide genotyped participants with type 2 diabetes who had undergone coronary angiograms. RESULTS:In the UK Biobank we found that the CHD PRS was strongly associated with CHD amongst individuals with type 2 diabetes (OR per standard deviation increase = 1.50; p = 1.5 × 10- 59). But this CHD PRS was, at best, only weakly associated with traditional clinical risk factors, such as hypertension, hyperlipidemia, glycemic control, obesity and smoking. Conversely, in the angiographic cohort, the CHD PRS was strongly associated with multivessel stenosis (OR = 1.65; p = 4.9 × 10- 4) and increased number of major stenotic lesions (OR = 1.35; p = 9.4 × 10- 3). CONCLUSIONS:Polygenic predisposition to CHD is strongly associated with atherosclerotic burden in individuals with type 2 diabetes and this effect is largely independent of traditional clinical risk factors. This suggests that genetic risk for CHD acts through atherosclerosis with little effect on most traditional risk factors, providing the opportunity to explore new biological pathways.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:By binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe-/- mice and IgE-deficient Ige-/- mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe-/-Ige-/- mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency. CONCLUSIONS:IgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.

背景与目标：

BACKGROUND & AIMS: :Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions.

背景与目标： 中性粒细胞与动脉粥样硬化的发病机制有关，但很少在动脉粥样硬化斑块中检测到。我们调查了中性粒细胞来源的微泡是否会影响动脉病理生理学。在这里，我们报告了通过暴露于高脂饮食 (一种已知的动脉粥样硬化危险因素) 来提高循环中性粒细胞微泡的水平。中性粒细胞微泡在暴露于紊乱血流模式的动脉易患病区域积聚，并在鼠模型中促进血管炎症和动脉粥样硬化。使用暴露于扰动流的培养的内皮细胞，我们证明中性粒细胞微泡通过递送miR-155促进炎症基因表达，增强NF-κ b活化。同样，中性粒细胞微泡增加miR-155，并在体内流动紊乱的易发部位增强NF-κ b。中性粒细胞微泡对动脉粥样硬化斑块形成的增强和巨噬细胞含量的增加取决于miR-155。我们得出的结论是，中性粒细胞通过将携带miR-155的微泡递送到易患疾病的区域而导致血管炎症和动脉粥样硬化。

BACKGROUND & AIMS: PURPOSE:Atherosclerosis is a progressive process that initially involves endothelial dysfunction. We investigated the effects of atorvastatin on both lipid parameters, and VCAM-1 and ICAM-1 expression in apoE-deficient or wild type C57BL/6J mice. METHODS:The C57BL/6J mice were fed with either chow or an atherogenic diet for 12 weeks. Male apoE-deficient mice were fed with the chow diet for 12 weeks. In 3 atorvastatin treated groups mice were fed the same diet as described above except atorvastatin was added to the diet at the dosage of 10 mg/kg per day for the last 8 weeks before euthanasia. RESULTS:Biochemical analysis showed that atorvastatin significantly decreased total cholesterol levels and VLDL in C57BL/6J mice fed with atherogenic diet but increased serum lipid levels in apoE-deficient mice. Stereological analysis of the immunohistochemical staining revealed that atorvastatin reduced endothelial expression of ICAM-1 and VCAM-1 only in C57BL/6J mice on chow diet. CONCLUSION:We have demonstrated that endothelial expression of both VCAM-1 and ICAM-1 does not correlate with cholesterol levels in these mice. Moreover, we showed that 8-week administration of atorvastatin decrease endothelial expression of VCAM-1 and ICAM-1 in C57BL/6J wild type mice beyond its lipid lowering effect but not in C57BL/6J wild type mice fed by atherogenic diet or in apoE-deficient mice.

背景与目标：

BACKGROUND & AIMS: :Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE-/-) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE-/- mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE-/- mice that were indistinguishable from rhythms in ApoE+/+ mice. These data showed that ApoE-/- mice had no inherent circadian disruption and therefore were an appropriate model for our study. We next induced severe disruption of circadian rhythms by exposing ApoE-/- mice to constant light for 12 weeks. Constant light exposure exacerbated atherosclerosis in male, but not female, ApoE-/- mice. Male ApoE-/- mice exposed to constant light had increased serum cholesterol concentrations due to increased VLDL/LDL fractions. Taken together, these data suggest that ApoE-/- mice are an appropriate model for studying light-induced circadian disruption and that exacerbated dyslipidemia may mediate atherosclerotic lesion formation caused by constant light exposure.

背景与目标： : 在现代社会中，由于光线的紊乱而引起的昼夜节律系统的破坏普遍存在，并增加了患心血管疾病的风险。发生这种情况的机制在很大程度上是未知的。载脂蛋白缺乏 (ApoE-/-) 小鼠通常被研究以阐明动脉粥样硬化的机制。在这项研究中，我们确定了光诱导的昼夜节律破坏对ApoE-/-小鼠动脉粥样硬化的影响。我们首先表征了ApoE-/-小鼠组织中行为的昼夜节律，光反应性和分子计时，这些节律与ApoE/小鼠的节律没有区别。这些数据表明ApoE-/-小鼠没有固有的昼夜节律破坏，因此是我们研究的合适模型。接下来，我们通过将ApoE-/-小鼠暴露于持续的光照下12周，导致昼夜节律的严重破坏。持续的光照会加剧雄性ApoE-/-小鼠的动脉粥样硬化，但不是雌性。由于VLDL/LDL分数增加，暴露于恒定光下的雄性ApoE-/-小鼠的血清胆固醇浓度增加。综上所述，这些数据表明ApoE-/-小鼠是研究光诱导的昼夜节律破坏的合适模型，并且加剧的血脂异常可能介导由持续的光照引起的动脉粥样硬化病变的形成。

BACKGROUND & AIMS: :This manuscript describes sequential angiographic, endothelial and vasoreactivity characteristics of the coronary arterial circulation in a middle-aged patient with multiple cardiac risk factors who developed hemodynamically significant coronary atherosclerosis over a 6-year period. A 56-year-old woman demonstrated marked angiographic progression of coronary atherosclerosis over time beginning with minor luminal irregularities in the setting of severe endothelial dysfunction. The association of endothelial dysfunction, ineffective cardiac risk factor management and progressive atherosclerosis is discussed.

背景与目标： : 该手稿描述了一名患有多种心脏危险因素的中年患者的冠状动脉循环的顺序血管造影，内皮和血管反应性特征，这些患者在6年内发生了血流动力学显着的冠状动脉粥样硬化。一名56岁的女性表现出冠状动脉粥样硬化的明显血管造影进展，随着时间的推移，在严重的内皮功能障碍的情况下开始出现轻微的管腔不规则。讨论了内皮功能障碍，无效的心脏危险因素管理与进展性动脉粥样硬化的关系。

BACKGROUND & AIMS: :Of all the risk factors to cardiovascular disease (CVD), age is the most powerful: CVD incidence and prevalence rise progressively at all ages beyond young adulthood. This reflects the central role of time, and hence duration, in the atherogenic process. It also reflects age-related changes in physiology - notably alterations in body mass and composition favoring increased adiposity and in sex hormone secretion (combining adverse effects of androgens on lipoprotein lipid levels in males, lowering HDL, and of the decline in estrogens in postmenopausal females, raising LDL). The interactions among the passage of time, these physiological changes and perhaps aging per se, and pathological forces such as cigarette smoking, hypertension, and genetically determined dyslipoproteinemia conspire to accelerate the rate of atherogenesis. Thus clinical atherosclerosis and its complications rise exponentially with increasing age in the population at large. However, the relationship between dyslipoproteinemia and CVD risk in the individual patient actually declines with advancing age. This apparent paradox reflects confounding introduced by the advent of disease processes that cause wasting and inflammation such as cancer, infection, diabetes, trauma, and even CVD that actually lower lipid levels, frequently to the level of hypocholesterolemia. Thus, while with age the population-attributable risk of hypercholesterolemia (and/or low HDL) rises, the cholesterol-attributable risk in the individual falls. As a result the prescription of lipid-lowering therapy in elderly patients requires exquisite individualization: patients most likely to benefit are those with existing CVD (i.e., in secondary prevention) who nevertheless enjoy robust health and are highly motivated to comply with demanding regimens of diet and exercise plus drugs where needed to reach target LDL levels (less than 100 mg/dl). At the other extreme are those least likely to benefit: patients who are frail and failing from CVD or other wasting diseases of old age that present a more immediate threat to survival.

背景与目标： : 在心血管疾病 (CVD) 的所有危险因素中，年龄是最强大的: CVD的发病率和患病率在成年后的所有年龄段都逐渐上升。这反映了时间以及持续时间在动脉粥样硬化过程中的核心作用。它还反映了与年龄相关的生理变化-特别是体重和组成的变化，有利于肥胖和性激素分泌增加 (结合雄激素对男性脂蛋白脂质水平的不利影响，降低HDL和雌激素的下降) 绝经后女性，提高LDL)。时间的流逝，这些生理变化以及可能的衰老本身以及诸如吸烟，高血压和遗传决定的血脂异常等病理力量之间的相互作用共同加速了动脉粥样硬化的发生速度。因此，随着人口年龄的增长，临床动脉粥样硬化及其并发症呈指数增长。然而，个体患者的血脂蛋白血症与CVD风险之间的关系实际上随着年龄的增长而下降。这种明显的悖论反映了由引起消瘦和炎症的疾病过程的出现所引起的混淆，例如癌症，感染，糖尿病，创伤甚至CVD，这些疾病实际上降低了脂质水平，通常降低到了低胆固醇血症的水平。因此，随着年龄的增长，高胆固醇血症 (和/或低HDL) 的人群归因风险上升，个体的胆固醇归因风险下降。因此，老年患者的降脂治疗处方需要精巧的个体化: 最有可能受益的患者是患有CVD的患者 (即，在二级预防中)，尽管如此，他们仍然享有健康，并且在需要达到目标LDL水平 (低于100 mg/dl) 的情况下高度积极地遵守饮食和运动加药物的要求。另一个极端是那些最不可能受益的人: 虚弱且因CVD或其他老年消耗性疾病而失败的患者，这些患者对生存构成了更直接的威胁。

BACKGROUND & AIMS: :Type 2 diabetes mellitus is a condition associated with an increased risk of coronary artery disease. This condition is currently reaching epidemic proportions in the Western world. Epidemiological studies have shown that insulin resistance and the constellation of metabolic alterations associated with type 2 diabetes mellitus such as dyslipidaemia, systemic hypertension, obesity and hypercoagulability, have an effect on the premature onset and severity of atherosclerosis. Albeit direct, the link between insulin resistance and atherogenesis is rather complex. It is likely that its complexity relates to the interaction between genes that predispose to insulin resistance and genes that independently regulate lipid metabolism, coagulation processes and biological responses of the arterial wall. The rapid development of molecular biology in recent years has resulted in a better understanding of the immune and inflammatory mechanisms that underlie insulin resistance and atherosclerosis. For example, it is known that nuclear transcription factors such as nuclear factor kappa beta and peroxisome proliferator-activated receptor are involved in atherosclerosis. The former modulates gene expression which encodes pro-inflammatory proteins vital for the development of the atheromatous plaque. In the presence of insulin resistance there are multiple activating factors that could explain the early onset and severity of atherosclerosis. Glitazones, the new oral antidiabetic drugs and agonists of peroxisome proliferator-activated receptor, have been shown to improve peripheral insulin sensitivity and to also delay atherosclerosis progression in experimental models. Their beneficial effects have been linked to their anti-inflammatory effect.

背景与目标： 2型糖尿病是一种与冠状动脉疾病风险增加相关的疾病。这种情况目前在西方世界已达到流行病的程度。流行病学研究表明，胰岛素抵抗和与2型糖尿病相关的代谢改变的星座，例如血脂异常，全身性高血压，肥胖和高凝状态，对动脉粥样硬化的过早发作和严重程度有影响。尽管是直接的，但胰岛素抵抗与动脉粥样硬化之间的联系相当复杂。它的复杂性可能与易引起胰岛素抵抗的基因与独立调节脂质代谢，凝血过程和动脉壁生物学反应的基因之间的相互作用有关。近年来，分子生物学的快速发展使人们对胰岛素抵抗和动脉粥样硬化的免疫和炎症机制有了更好的了解。例如，已知核转录因子如核因子 κ β 和过氧化物酶体增殖物激活受体参与动脉粥样硬化。前者调节基因表达，该基因编码对动脉粥样硬化斑块的发展至关重要的促炎蛋白。在存在胰岛素抵抗的情况下，存在多种激活因子可以解释动脉粥样硬化的早期发作和严重程度。在实验模型中，新的口服抗糖尿病药物和过氧化物酶体增殖物激活受体激动剂格列酮已被证明可以改善外周胰岛素敏感性并延缓动脉粥样硬化的进展。它们的有益作用与抗炎作用有关。

BACKGROUND & AIMS: :We investigated the protective effects of the traditional Japanese herbal medicine Saiko-ka-ryukotsu-borei-to (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang in Chinese) (SRBT) against hypercholesterolemia and atherosclerotic lesions. We focused on atherosclerosis using female heterozygous Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. The total plasma cholesterol levels increased for up to 12 weeks after beginning a diet containing 0.1% cholesterol and then reached a plateau of about 600 mg dl(-1). When SRBT was administered at a dose of 1.0 g kg(-1)per day for 24 weeks, total plasma cholesterol levels were significantly decreased after 20-24 weeks. On the other hand, pravastatin at a dose of 10 mg kg(-1)per day produced a significant decrease in total plasma cholesterol levels from 4 to 24 weeks (about 105-130 mg dl(-1)). Moreover, 1.0 g kg(-1)per day of SRBT significantly decreased plasma low density lipoprotein (LDL) cholesterol levels but did not change either very low density lipoprotein (VLDL), or high density lipoprotein (HDL) cholesterol levels. Animals that received pravastatin had significantly decreased LDL cholesterol levels and VLDL cholesterol levels after 8 weeks and at 24 weeks. We also examined the expression of apoB, E and LDL receptor mRNA levels in the liver at 24 weeks after beginning the administration of 1.0 g kg(-1)per day of SRBT. Both apoE and LDL receptor mRNA levels were significantly increased compared with those in rabbits receiving the 0.1% cholesterol diet. SRBT at a dose of 1.0 g kg(-1)per day significantly depressed the intimal surface area of the thoracic aortae involved with atheromatous plaques. The present results suggest that SRBT may protect against hypercholesterolemia and atheromatous lesions by affecting apoE and LDL receptor mRNA gene expression in the liver.

背景与目标： : 我们研究了日本传统草药Saiko-ka-ryrokotsu-borei-too (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang中文) (SRBT) 对高胆固醇血症和动脉粥样硬化的保护作用病变。我们使用雌性杂合子黑泽和草木高胆固醇血症 (KHC) 兔专注于动脉粥样硬化。在开始含有0.1% 胆固醇的饮食后，总血浆胆固醇水平增加长达12周，然后达到约600 mg dl(-1) 的平台期。当以每天1.0g kg(-1) 的剂量施用SRBT持续24周时，总血浆胆固醇水平在20-24周后显着降低。另一方面，每天10 mg kg(-1) 剂量的普伐他汀在4至24周期间产生了总血浆胆固醇水平的显著降低 (约105-130 mg dl(-1))。此外，每天1.0 gkg (-1) 的SRBT显着降低血浆低密度脂蛋白 (LDL) 胆固醇水平，但不改变极低密度脂蛋白 (VLDL) 或高密度脂蛋白 (HDL) 胆固醇水平。接受普伐他汀的动物在8周和24周后显着降低了LDL胆固醇水平和VLDL胆固醇水平。我们还检查了在开始每天施用1.0g kg(-1) SRBT后24周肝脏中apoB，E和LDL受体mRNA水平的表达。与接受0.1% 胆固醇饮食的兔子相比，apoE和LDL受体mRNA水平均显着增加。每天1.0g kg(-1) 的SRBT显着降低了动脉粥样斑块累及的胸主动脉的内膜表面积。目前的结果表明，SRBT可以通过影响肝脏中apoE和LDL受体mRNA基因的表达来预防高胆固醇血症和动脉粥样硬化病变。

BACKGROUND & AIMS: :Increased secretion and levels of ApoB-containing lipoproteins (BLp) commonly occur in familial hyperlipidemia, obesity and diabetes. The plasma phospholipid-transfer protein (PLTP) is known to mediate transfer of phospholipids between BLp and HDL during their intravascular metabolism. To address a possible role of PLTP in dyslipidemia and atherogenesis, we bred mice deficient in the gene encoding PLTP (PLTP-deficient mice) using different hyperlipidemic mouse strains. In ApoB-transgenic and ApoE-deficient backgrounds, PLTP deficiency resulted in reduced production and levels of BLp and markedly decreased atherosclerosis. BLp secretion was diminished in hepatocytes from ApoB-transgenic PLTP-deficient mice, a defect that was corrected when PLTP was reintroduced in adenovirus. The studies reveal a major, unexpected role of PLTP in regulating the secretion of BLp and identify PLTP as a therapeutic target.

背景与目标： : 含ApoB脂蛋白 (BLp) 的分泌和水平增加通常发生在家族性高脂血症，肥胖症和糖尿病中。已知血浆磷脂转移蛋白 (PLTP) 在其血管内代谢过程中介导磷脂在BLp和HDL之间的转移。为了解决PLTP在血脂异常和动脉粥样硬化中的可能作用，我们使用不同的高脂血症小鼠品系繁殖了缺乏编码PLTP基因的小鼠 (PLTP缺陷型小鼠)。在ApoB转基因和ApoE缺乏的背景下，PLTP缺乏导致BLp的产生和水平降低，并显着降低动脉粥样硬化。来自ApoB转基因PLTP缺陷小鼠的肝细胞中BLp分泌减少，当PLTP在腺病毒中重新引入时，该缺陷得到了纠正。研究揭示了PLTP在调节BLp分泌中的重要而出乎意料的作用，并将PLTP确定为治疗靶标。

BACKGROUND & AIMS: :Peroxisome proliferator-activated receptor-alpha is widely distributed in the vasculature where it is believed to exert pleiotropic antiatherogenic effects. Its role in the regulation of blood pressure is still unresolved; however, some evidence suggests that it may affect the renin-angiotensin system. We investigated its role in angiotensin II-induced hypertension in the Tsukuba hypertensive mouse (THM). This is a model of hypertension and atherosclerosis because of high angiotensin II and aldosterone levels as a result of the transgenic expression of the entire human renin-angiotensin system. Making the THM animals deficient in Peroxisome proliferator-activated receptor-alpha (THM/PPARKO) totally abolished hypertension and myocardial hypertrophy. This was accompanied by a reduction in plasma human active renin in THM/PPARKO mice compared with THM animals from 3525+/-128 mU/L to 1910+/-750 mU/L (P<0.05) and by a normalization of serum aldosterone (1.6+/-0.29 nmol/L versus 3.4+/-0.69 nmol/L; P=0.003). In the THM/PPARKO mice, the extent of atherosclerosis at the aortic sinus after a 12-week period on an atherogenic diet was decreased by >80%. In addition, the spontaneous formation of foam cells from peritoneal macrophages, a blood pressure-independent event, was reduced by 92% in the THM/PPARKO mice, suggesting protection from the usual oxidative stress in these animals, possibly because of lower prevailing angiotensin II levels. Finally, chronic fenofibrate treatment further elevated blood pressure in THM animals but not in THM/PPARKO animals. Taken together, these data indicate that peroxisome proliferator-activated receptor-alpha may regulate the renin-angiotensin system. They raise the possibility that its activation may aggravate hypertension and hasten atherosclerosis in the context of an activated renin-angiotensin system.

背景与目标： : 过氧化物酶体增殖物激活的受体 α 广泛分布在脉管系统中，据信它具有多效性抗动脉粥样硬化作用。它在血压调节中的作用仍未解决; 但是，一些证据表明它可能会影响肾素-血管紧张素系统。我们研究了其在筑波高血压小鼠 (THM) 中血管紧张素II诱导的高血压中的作用。这是高血压和动脉粥样硬化的模型，因为整个人肾素-血管紧张素系统的转基因表达导致血管紧张素II和醛固酮水平升高。使过氧化物酶体增殖物激活受体 α (THM/PPARKO) 缺乏的THM动物完全消除了高血压和心肌肥大。与THM动物相比，THM/PPARKO小鼠血浆人活性肾素从3525 +/-128 mU/L 1910年 +/-750 mU/L (P<0.05) 降低，血清醛固酮正常化 (1.6 +/-0.29 nmol/L对3.4 +/-0.69 nmol/L; P = 0.003)。在THM/PPARKO小鼠中，在致动脉粥样硬化饮食12周后，主动脉窦处的动脉粥样硬化程度降低> 80%。此外，在THM/PPARKO小鼠中，92% 减少了来自腹膜巨噬细胞的泡沫细胞的自发形成，这是一种与血压无关的事件，这表明保护了这些动物免受通常的氧化应激，这可能是由于较低的主要血管紧张素II水平。最后，慢性非诺贝特治疗进一步提高了THM动物的血压，但没有提高THM/PPARKO动物的血压。总之，这些数据表明过氧化物酶体增殖物激活的受体 α 可能调节肾素-血管紧张素系统。在激活的肾素-血管紧张素系统的背景下，它们增加了其激活可能加剧高血压并加速动脉粥样硬化的可能性。

BACKGROUND & AIMS: :Background Chronic kidney disease is associated with structural and compositional abnormalities in high-density lipoprotein particles (HDLp). We examined associations of HDLp size, particle subfractions, and apolipoprotein C-III content with incident cardiovascular disease (CVD) events across categories of estimated glomerular filtration rate (eGFR). Methods and Results Analyses included 6699 participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of HDLp and 5723 participants with measurements of HDL apolipoprotein C-III. Cox-regression methods were used to evaluate associations between HDLp and apolipoproteins with CVD events. Larger HDLp size was associated with lower CVD risk in participants with lower eGFR: hazard ratio (95% CI) per SD higher mean HDL size was 1.00 (0.90-1.11) in eGFR ≥60 mL/min per 1.73 m2, 0.65 (0.48-0.86) in eGFR 45 to 59 mL/min per 1.73 m2, and 0.48 (0.25-0.93) in eGFR <45 mL/min per 1.73 m2 (P for interaction=0.05). Associations of HDLp subfractions with CVD varied significantly by eGFR (P for interaction=0.04), with significant inverse associations between higher concentrations of large HDLp and CVD events across categories of kidney function, but nonsignificant results for small HDLp. Only HDLp without apolipoprotein C-III was associated with lower risk of CVD events, with seemingly (albeit not statistically significant) stronger associations among participants with lower eGFR (P for interaction=0.19). Conclusions HDL particles of larger size and higher concentrations of large HDL and of HDL without apolipoprotein C-III were associated with lower CVD risk, with risk estimates seemingly stronger among participants with lower eGFR. Future larger studies are needed to corroborate these findings.

背景与目标： 背景: 慢性肾脏疾病与高密度脂蛋白颗粒 (HDLp) 的结构和组成异常有关。我们检查了HDLp大小，颗粒亚组分和载脂蛋白C-III含量与估计肾小球滤过率 (eGFR) 类别的心血管疾病 (CVD) 事件的相关性。方法和结果分析包括在MESA (多种族动脉粥样硬化研究) 中测量HDLp的6699名参与者和在HDL载脂蛋白c-iii测量的5723名参与者。Cox回归方法用于评估HDLp和载脂蛋白与CVD事件之间的关联。在eGFR: 风险比 (95% CI)/SD较低的参与者中，较大的HDLp大小与较低的CVD风险相关。在eGFR ≥ 60 ml/min/1.73平方米中，较高的平均HDL大小为1.00 (0.90-1.11)。0.65 (0.48-0.86) 在eGFR 45至59 ml/min/1.73平方米中，0.48 (0.25-0.93) 在eGFR <45 ml/min/1.73平方米中 (相互作用P = 0.05)。HDLp亚组分与CVD的关联因eGFR而显著变化 (相互作用的P = 0.04)，在较高浓度的大HDLp与跨肾功能类别的CVD事件之间存在显著的反向关联，但对于小HDLp则无显著结果。只有没有载脂蛋白c-iii的HDLp与较低的CVD事件风险相关，在eGFR较低的参与者之间似乎 (尽管无统计学意义) 更强的关联 (相互作用P = 0.19)。结论较大尺寸的HDL颗粒和较高浓度的大HDL和没有载脂蛋白c-iii的HDL与较低的CVD风险相关，在eGFR较低的参与者中，风险估计似乎更强。需要未来更大的研究来证实这些发现。

BACKGROUND & AIMS: BACKGROUND:Omentin and adiponectin are among the anti-inflammatory and anti-atherogenic adipokines that have potentially beneficial effects on cardiovascular disorders. Recent studies indicate a paradoxical relationship between adiponectin and cardiovascular mortality across many clinical settings including type 2 diabetes. In this study, we characterized the clinical features of type 2 diabetes patients with increased adiponectin levels and examined the association between omentin and atherosclerosis in those patients. METHODS:The subjects were 413 patients with type 2 diabetes. Fasting plasma omentin and total adiponectin levels were measured by enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasonography. The subjects were stratified according to the median value of plasma adiponectin. RESULTS:In high-adiponectin group, omentin levels were higher, while IMT tended to be greater than those in low-adiponectin group. The high-adiponectin group also exhibited older age, higher systolic blood pressure, lower kidney function, body mass index, and insulin resistance index compared to the low-adiponectin group. Multivariate analysis revealed that omentin levels were independently and negatively associated with IMT in high-adiponectin group, but not in low-adiponectin group, after adjusting for adiponectin levels and traditional cardiovascular risk factors. On the other hand, adiponectin levels were not significantly associated with IMT in either group. CONCLUSIONS:Plasma omentin levels are inversely associated with IMT in type 2 diabetes patients with increased adiponectin levels and multiple cardiovascular risk factors. This study suggests a protective role of omentin against atherosclerosis in type 2 diabetes patients, which is potentially influenced by adiponectin level and cardiovascular risk status.

背景与目标：