原发性高血压患者单核细胞趋化蛋白-1基因多态性对尼索地平疗效的影响

目的探究并分析原发性高血压(高血压)患者单核细胞趋化蛋白-1(monocyte chemoattractant protein-1,MCP-1)基因多态性与尼索地平疗效及血清整合素β3、血清细胞间黏附分子(serum intercellular adhesion molecule,sICAM)-1浓度的相关性。方法选取2017年3月至2018年3月成都市温江区人民医院收治的高血压患者100例(基因型为-2076A/T或者-2518G/A),根据患者基因检测结果分为观察组(基因型-2076A/T)及对照组(基因型-2518G/A)。两组患者均给予尼索地平治疗,观察并记录两组患者治疗前,治疗后1个月,治疗后3个月血压控制情况以及血清整合素β3、sICAM-1浓度。结果两组患者性别、年龄、体质量、病程、用药等比较,差异无统计学意义(P>0.05)。治疗后两组患者血压、整合素β3浓度、sICAM-1浓度均较治疗前明显降低,差异有统计学意义(P<0.05),但观察组患者血压、整合素β3浓度、sICAM-1浓度降低程度显著高于对照组,差异有统计学意义(P<0.05)。观察组患者总有效率显著高于对照组,差异有统计学意义(P<0.05)。结论采用尼索地平治疗后,MCP-1基因型为-2076A/T的高血压患者的疗效及血清整合素β3、sICAM-1浓度降低程度显著高于MCP-1基因型为-2518G/A的高血压患者。     

原发性高血压患者炎症因子表达水平及其与血管紧张素Ⅱ的关系

目的 :探讨原发性高血压 (EH)患者血浆中炎症因子单核细胞趋化因子 1(MCP 1)和P 选择素的表达水平以及与血管紧张素Ⅱ (AngⅡ )的关系。 方法 :用ELISA法检测 32例EH患者 (EH组 )和 30例健康者 (对照组 )血浆MCP 1和P 选择素 ,同时用放射免疫法测定其血浆中AngⅡ水平。结果 :与对照组相比 ,EH组患者血浆中MCP 1和P 选择素水平明显升高 [分别为 (18.6 6± 2 .5 5 )∶(15 .4 5± 1.13)ng/L ,(11.4 3± 3.35 )∶(3.4 7±1.31)ng/L ,均P <0 .0 5 ],但与血浆AngⅡ浓度以及血压升高的程度无相关性。结论 :EH患者血浆中炎性因子MCP 1和P 选择素浓度明显增加 ,这可能与高血压促动脉粥样硬化的发生发展有关     

Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes

Homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are major chemokines for leukocyte trafficking and have been identified in atheromatous plaques. MCP-1 and IL-8 have been found to express mainly by macrophages in human lesion. We undertook this study to determine whether Hcy could induce the secretion of chemokines from human monocytes and, if so, to explore the mediating mechanism. We found that clinically relevant levels of Hcy (10 to 1000 micromol/L) increased the protein secretion and mRNA expression as well as activity of MCP-1 and IL-8 in cultured primary human monocytes. These effects of Hcy were primarily mediated by reactive oxygen species (ROS) through NAD(P)H oxidase, because Hcy could upregulate the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers, or NAD(P)H oxidase abolished Hcy-induced ROS production and MCP-1 and IL-8 secretion in these cells. Furthermore, the inhibitors of mitogen-activated protein kinase (p38 and extracellular signal-regulated kinase 1/2) and nuclear factor-kappaB or the activator of peroxisome proliferator-activated receptor gamma (PPARgamma) significantly decreased Hcy-induced MCP-1 and IL-8 secretion in these cells. These data indicate that pathophysiological levels of Hcy can alter human monocyte function by upregulating MCP-1 and IL-8 expression and secretion via enhanced formation of intracellular ROS originated from NAD(P)H oxidase source via calmodulin or protein kinase C signaling pathways and that Hcy-induced ROS subsequently activates mitogen-activated protein kinase (p38 and ERK1/2) and nuclear factor-kappaB in a PPARgamma activator-sensitive manner. Thus, activation of PPARgamma may become a therapeutic target for preventing Hcy-induced proatherogenic effects.     

HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes

The mechanism whereby HIV-infected cells transit from the bloodstream into tissues is not well defined. This phenomenon was addressed by studying the effects of HIV-1 Tat, a protein secreted by infected cells, on human lung microvascular endothelial cells (HMVEC-Ls). It was found that monocyte chemoattractant protein-1 (MCP-1) was released from HMVEC-Ls in a dose- and time-dependent manner after Tat treatment. MCP-1 is a potent beta-chemokine that recruits monocytes and T cells and promotes cell adhesion and transmigration across an endothelial monolayer. It was also observed that MCP-1 and the culture medium from Tat-treated HMVEC-Ls were chemotactic for CD14(+) monocytes from human peripheral blood and for THP-1, a promonocytic cell line used as a model system. To characterize the signaling pathways underlying the observed induction of MCP-1, HMVEC-Ls were treated with 2 different protein kinase inhibitors: PD98059, a MAP kinase inhibitor, and GF109203X, a protein kinase C (PKC) inhibitor. MCP-1 release was significantly reduced when PKC was inhibited, and slightly decreased when PI3 kinase was blocked; no effect on MCP-1 release was observed on MAP kinase inhibition. Similarly, transmigration of THP-1 cells was significantly impaired by the PKC inhibitor, but not by the other tested inhibitors. These data indicate that the HIV-1 Tat protein may act as a protocytokine by causing the release of MCP-1 from the endothelial monolayer, and thereby facilitating monocyte transmigration into tissues via a PKC signaling pathway.     

结直肠癌趋化因子单核细胞超化蛋白-1的表达

目的：通过检测结直肠癌组织中单核细胞超化蛋白－1（MPC－1）的表达情况，研究MCP－1的表达与结直肠癌生物学行为的关系。方法：采用RT－PCR方法，检测临床收集的新鲜结肠癌组织标本中MCP－1mRNA的表达；采用免疫组化方法，检测结直肠癌组织中MCP－1蛋白的表达，结果：12例结直肠癌组织均可出现MCP－1mRNA的表达，40例结直肠癌组织MCP－1蛋白表达的阳性率为90％，结直肠癌组织MCP－1蛋白的表达与结直肠癌的转移及Dukes分期有关，表达强者，转移发生率低，Dukes分期早，结论：结直肠组织中MCP－1的表达能影响结直肠癌的生物学行为。     

脱氢表雄酮及趋化因子蛋白-1在动脉粥样硬化组织中表达的相关性研究

目的:研究脱氢表雄酮(DHEA)与单核细胞趋化因子蛋白-1(MCP-1)在动脉粥样硬化组织中的表达相关性,及其与动脉粥样硬化发生发展的关系,为寻找临床治疗的新靶点提供依据。方法:将纳入本研究的130例尸检患者的冠状动脉,做常规石蜡切片,根据病理镜下诊断分为动脉粥样硬化组80例和正常冠状脉对照组50例,利用免疫组化方法同步检测动脉粥样硬化组和正常对照组中DHEA与MCP-1的表达,分析DHEA、MCP-1与冠状动脉粥样硬化发生发展的关系以及DHEA与MCP-1的相关性。结果:动脉粥样硬化组较正常对照组DHEA表达水平显著下降(χ~2=52. 82,P0. 05)。动脉粥样硬化组较正常对照组MCP-1表达水平显著升高(χ~2=29. 73,P0. 05)。DHEA与MCP-1在动脉粥样硬化组织中表达呈负相关(r=-0. 311,P0. 05)。结论:DHEA和MCP-1参与了冠状动脉粥样硬化的形成过程,并发挥着不同的调节作用。     

过氧化物酶体增殖物激活受体对哮喘患者树突状细胞免疫调控的影响

支气管哮喘是以Th1/Th2细胞比例失衡和Th2细胞优势分化为免疫学发病基础的慢性气道炎症性疾病。树突状细胞(DC)在哮喘发病中起重要作用,髓系DC(DC1)能促使支气管哮喘原始Th细胞向Th2细胞分化增殖,肺脏淋巴系DC(肺脏DC2)能诱导免疫耐受;过氧化物酶体增殖物激活受体-γ(PPAR-γ)能减轻哮喘气道炎症。因此,我们综述了PPAR-γ对哮喘患者DC免疫调控功能的影响,为哮喘的研究防治探索新思路。     

Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1), a pro-inflammatory chemokine, has potent chemoattractant activity for monocytes/macrophages. We sought to investigate the clinical significance of MCP-1 in idiopathic pulmonary arterial hypertension (IPAH). METHODS: This study included 28 patients with IPAH, seven patients with pulmonary arterial hypertension (PAH) related to collagen vascular disease, and 13 healthy subjects. Plasma MCP-1 levels were measured together with serum IL-6 and tumour necrosis factor-alpha (TNF-alpha) levels. RESULTS: Circulating levels of MCP-1, IL-6 and TNF-alpha were significantly higher in patients with IPAH than in healthy controls, although they were lower than in patients with PAH related to collagen vascular disease. Plasma MCP-1 did not significantly correlate with any haemodynamic variables. However, plasma MCP-1 levels correlated negatively with the disease duration (time from symptom onset). CONCLUSIONS: Plasma MCP-1 levels were elevated in patients with IPAH, and this elevation was particularly marked in the early stage of disease. Taking into account the chemoattractant activity of MCP-1, these results imply a contribution of MCP-1 to the development of pulmonary hypertension.     

Preactivated peripheral blood monocytes in patients with essential hypertension.

The purpose of this study was to investigate the possible involvement of human peripheral blood monocytes in the pathology of hypertensive disease. We determined the in vitro secretion patterns of proinflammatory cytokines obtained from isolated peripheral monocytes from normal controls and from hypertensive patients either after in vitro stimulation with angiotensin II (Ang II) with or without preincubation with an Ang II type 1 receptor antagonist (losartan) or after stimulation with lipopolysaccharide. Blood samples were obtained from 22 patients with essential hypertension (before any drug administration or after interruption of antihypertensive therapy) and from 24 normotensive healthy individuals used as a control group. Peripheral blood monocytes were isolated by density gradient centrifugation and plastic adherence. The state of monocyte activity was determined by the capacity to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6, (IL-6) either spontaneously or after stimulation. Cytokine concentrations were determined in culture supernatants by specific ELISA. Proinflammatory cytokine levels were assessed by semiquantitative reverse transcribed polymerase chain reaction. After stimulation with Ang II, the IL-1beta secretion of peripheral blood monocytes was significantly increased in hypertensive patients versus healthy individuals (P<0.05). In contrast, in monocytes preincubated with losartan before exposure to Ang II, IL-1beta secretion was diminished in both groups to comparable levels. The secretion of IL-1beta and TNF-alpha was significantly increased in peripheral blood monocytes from hypertensive patients versus healthy individuals after stimulation with lipopolysaccharide (TNF-alpha, P<0.02; IL-1beta, P<0.05). Upregulation of IL-1beta and TNF-alpha secretion in peripheral blood monocytes from hypertensive patients was also seen at the RNA level. Our results indicate preactivated peripheral blood monocytes in hypertensive patients. Ang II may be directly involved in the process of monocyte activation.     

Effects of peroxisome proliferator-activated receptor-gamma activation with pioglitazone on plasma adipokines in nondiabetic patients with either hypercholesterolemia or hypertension

Adipokines are substances produced by the adipose tissue that may play significant roles in the mechanisms contributing to the development of atherosclerosis. Thiazolidinediones have been shown to improve endothelium-dependent vasodilation and to exert multiple antiatherosclerotic effects. This study tested the hypotheses that nondiabetic patients with cardiovascular risk factors have altered levels of adipokines that can be modified by pioglitazone treatment. Eighty patients with hypertension or hypercholesterolemia were in a double-blinded, placebo-controlled, crossover study. In each treatment phase, patients received pioglitazone 45 mg/day or placebo for 8 weeks. Endothelial function studies and biochemical assays were performed at the end of each 8-week treatment period. Twenty-two normal volunteers, matched with patients for age, gender, and body mass index, were recruited as a control group. Compared with controls, placebo-treated patients had lower adiponectin levels (11,160 +/- 763 vs 6,078 +/- 385 ng/ml, p <0.001) and similar plasma leptin levels (21.5 +/- 3.8 vs 16.2 +/- 1.5 ng/ml, p = 0.128) and resistin levels (5.1 +/- 0.4 vs 4.4 +/- 0.2 ng/ml, p = 0.250). In patients, pioglitazone treatment markedly increased adiponectin (+121%, p <0.001) and decreased resistin (-10.5%, p = 0.03). Leptin was not significantly decreased (-7.1%, p = 0.10). In multivariate analysis, pioglitazone-induced changes in endothelial reactivity to acetylcholine were the only significant predictor of increases in adiponectin. In conclusion, in nondiabetic patients with major cardiovascular risk factors, pioglitazone treatment beneficially influences circulating adipokine levels. The relation between the increase in adiponectin levels and the improvement in endothelial vasodilator activity suggests a mechanistic link between vascular effects and adiponectinemia.     

Epoprostenol therapy decreases elevated circulating levels of monocyte chemoattractant protein-1 in patients with primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension (PPH) is a rare disease characterized by progressively increased resistance of the pulmonary arteries associated with vascular remodeling. Infiltration of inflammatory cells in affected vessels is a common pathological finding. Monocyte chemoattractant protein-1 (MCP-1) is recognized as a potent chemotactic and activating factor for monocytes and leukocytes, but its significance in PPH is unclear. METHODS AND RESULTS: Serum MCP-1 concentrations were measured in 16 PPH patients and the results were compared with those in 16 normal controls. MCP-1 concentrations in PPH patients (265.6+/-29.5 pg/ml) were significantly elevated compared with those in normal controls (119.6+/-6.9 pg/ml, p<0.0001). In 9 patients (3 men, 6 women; mean age, 29+/-3 years), repeated MCP-1 and hemodynamic measurements were performed prior to and during intravenous epoprostenol therapy. During a mean follow-up period of 7+/-1 months, MCP-1 concentrations were significantly reduced (288.8+/-122.8 to 185.9+/-117.5 pg/ml, p<0.01). CONCLUSIONS: Circulating MCP-1 concentrations are increased in PPH patients, but can alleviated by chronic intravenous epoprostenol therapy. The increase in MCP-1 might be one of the important factors responsible for the disease development in patients with PPH.     

急性冠脉综合征患者外周血MCP-1和IL-18水平变化的临床意义

目的探讨急性冠脉综合征患者外周血单核/巨噬细胞趋化蛋白1(MCP-1)和白细胞介素18(IL-18)水平变化的意义及其相关性。方法酶联免疫吸附法测定30例急性冠脉综合征患者(急性冠脉综合征组),30例稳定型心绞痛患者(稳定型心绞痛组)及29例胸痛、胸闷等症状予以冠脉造影正常的患者(对照组)外周血MCP-1和IL-18水平的变化,并分析冠状动脉的病变情况。结果①急性冠脉综合征组MCP-1水平[(151.84±29.66)pg/ml]显著高于稳定型心绞痛组[(128.49±16.97)pg/ml,P<0.001]和对照组[(112.11±10.36)pg/ml,P<0.01],并且稳定型心绞痛组和对照组比较有统计学意义(0.0010.05)。④急性冠脉综合征组外周血MCP-1和IL-18呈明显正相关(r=0.519,P<0.01)。结论外周血MCP-1和IL-18水平可以判断冠心病的严重程度,能预测急性冠脉综合征发生的危险性,但与冠状动脉的病变程度无明显关系,MCP-1和IL-18的正相关提示因子间相互作用可能共同促进冠脉综合征的发生和发展。     

Differential regulation of macrophage peroxisome proliferator-activated receptor expression by glucose : role of peroxisome proliferator-activated receptors in lipoprotein lipase gene expression

Peroxisome proliferator-activated receptors (PPARs) are implicated in several metabolic disorders with altered glucose and lipid metabolism, including atherosclerosis and diabetes. In the present study, we evaluated the in vitro and ex vivo effects of high glucose concentrations on macrophage PPAR mRNA expression. Exposition of monocyte-derived macrophages isolated from healthy donors to a high glucose environment led to an increase in PPARalpha and PPARbeta mRNA expression. In contrast, this treatment significantly decreased human macrophage PPARgamma mRNA expression. Overexpression of PPARalpha and PPARbeta mRNA and inhibition of PPARgamma mRNA expression were also observed in monocyte-derived macrophages isolated from patients with type 2 diabetes. Because high glucose and PPARalpha agonists increase lipoprotein lipase (LPL) gene expression, the role of PPARalpha in the glucose-mediated upregulation of macrophage LPL gene expression was next evaluated. Incubation of murine J774 macrophages with high glucose concentrations increased the expression of PPARalpha at the mRNA and protein levels and enhanced nuclear protein binding to the peroxisome proliferator responsive element of the LPL promoter. Incubation of nuclear extracts in the presence of anti-PPARalpha and anti-PPARbeta antibodies decreased glucose-stimulated nuclear protein binding to the peroxisome proliferator responsive element. These results demonstrate that glucose is an important regulator of macrophage PPAR expression and suggest a role of PPARalpha and PPARbeta in the upregulation of macrophage LPL by glucose. Dysregulation of macrophage PPAR expression in type 2 diabetes may contribute, by altering arterial lipid metabolism and inflammatory response, to the accelerated atherosclerosis associated with diabetes.