血管生成素样蛋白3和4对脂质代谢和胰岛素抵抗的影响

血管生成素样蛋白(Angptl)3和Angptl4均是血管内皮生长因子家族成员。Angptl3在肝脏特异表达,而Angptl4主要在脂肪和肝脏表达,在心、肾等组织也有表达。Angptl3和Angptl4均可以通过抑制脂蛋白脂肪酶活性而调节脂质代谢,但在不同的营养状态下发挥作用。在胰岛素抵抗或胰岛素分泌缺陷时Angptl3的表达和血浆Angptl3水平明显升高,而血浆Angptl4水平在2型糖尿病患者是下降的。动物实验中给予外源性Angptl4可明显降低血糖浓度、改善机体葡萄糖耐量,提示它们与胰岛素抵抗有重要关系。     

血清血管生成素样蛋白2水平与2型糖尿病大血管并发症的相关性研究

[提要]本文主要探讨人血清血管生成素样蛋白2(Angptl 2)是否与2型糖尿病大血管并发症相关.研究发现对照组、2型糖尿病有或无颈动脉粥样硬化组的血清Angptl 2浓度有统计学差异[0.98(0.82～1.22)、3.70(2.69 ～4.85)、1.17(0.76～ 2.47) ng/ml].Logistic回归显示血清Angptl 2作为独立因素影响2型糖尿病患者大血管并发症的发生发展.     

血清Angptl2/Angptl1比值与稳定型心绞痛患者急性心肌梗死发生风险的相关性分析

目的探究血清血管生成素样蛋白2/血管生成素样蛋白1(Angptl2/Angptl1)比值在稳定型心绞痛患者急性心肌梗死的表达情况及与疾病发生风险的关系。方法选取2018年2月至2019年3月于西安高新医院接受治疗的205例稳定型心绞痛患者,根据住院期间是否发生急性心肌梗死分为对照组(126例)与急性心肌梗死组(79例),收集患者临床资料,采用酶联免疫吸附法检测血清中Angptl2、Angptl1水平,计算Angptl2/Angptl1比值;Pearson相关性分析Angptl2/Angptl1与冠状动脉病变评分的关系;采用Logistic分析影响稳定型心绞痛患者发生急性心肌梗死的危险因素,受试者工作特征曲线(ROC)评估Angptl2、Angptl2/Angptl1在稳定型心绞痛患者发生急性心肌梗死中的诊断价值。结果急性心肌梗死组高血压患病例数、饮酒例数、血清Angptl2、Angptl2/Angptl1水平均显著高于对照组,高密度脂蛋白(HDL)水平、Gensini积分显著低于对照组(P均<0.05),两组Angptl1水平无明显变化(P>0.05)。血清Angptl2、Angptl2/Angptl1与Gensini积分呈负相关,(r=-0.457,r=-0.384,P均<0.05)。高血压、Gensini积分、Angptl2、Angptl2/Angptl1是影响稳定型心绞痛患者发生急性心肌梗死的危险因素。Angptl2预测的稳定型心绞痛患者急性心肌梗死的AUC值为0.836(95%CI:0.778~0.884),敏感性71.38%,特异性82.74%;Angptl2/Angptl1对稳定型心绞痛患者急性心肌梗死预测的AUC值为0.877(95%CI:0.821~0.916),敏感性79.51%,特异性88.74%。结论稳定型心绞痛患者发生急性心肌梗死后血清Angptl2水平、Angptl2/Angptl1比值升高,Angptl1水平无明显变化,Angptl2、Angptl2/Angptl1在稳定型心绞痛患者发生急性心肌梗死中均具有一定的预测价值,Angptl2/Angptl1预测价值更优。     

血管生成素样因子-7在心血管疾病中的研究进展

血管生成素样因子（angiopoietin-like proteins,Angptls）是一类分泌性糖蛋白家族,与血管生成素（angiogenin,ANG）结构相似。血管生成素样因子-7(angiopoietin-like proteins 7,Angptl 7)是该家族成员之一,在血管生成、炎症反应、内皮细胞损伤、糖脂代谢紊乱、平滑肌细胞增殖中发挥重要作用,可能以此来参与心血管疾病的发生。本文主要就Angptl 7的来源与结构、功能特点及其在心血管疾病中的研究进展作一综述。     

不稳定型心绞痛病人血管生成素样蛋白2水平与冠状动脉粥样硬化斑块性质的关系研究

目的检测不稳定型心绞痛病人血管生成素样蛋白2(Angptl2)水平,并评价其与冠状动脉粥样硬化斑块性质的相关性。方法选取经多层螺旋CT血管成像(MSCTA)检测发现有冠状动脉粥样硬化斑块的40例不稳定型心绞痛病人和38例稳定型心绞痛病人进行Angptl2测定,分析血清Angptl2水平与斑块性质的相关性。结果不稳定型心绞痛组以混合性斑块和软斑块为主,稳定型心绞痛组以钙化斑块为主,两组斑块类型分布差异有统计学意义(P0.05);不稳定型心绞痛组血清Angptl2水平明显高于稳定型心绞痛组[(3.62±0.24)ng/mL与(2.80±0.16)ng/mL,P0.01];Angptl2水平在软斑块组[(4.72±0.35)ng/mL]和混合性斑块组[(4.36±0.52)ng/mL]均高于钙化斑块组[(3.42±0.43)ng/mL,P0.05)]。结论 Angptl2水平与不稳定型心绞痛病人冠状动脉粥样硬化斑块的性质有关,Angptl2水平升高有助于临床对动脉粥样硬化不稳定斑块的检测和诊断。     

血管生成素样蛋白-2与冠心病的研究进展

血管生成素样蛋白2是近年来发现的一种新兴分泌性蛋白,主要由内脏脂肪组织分泌,调节血管生成及各种抗炎、促炎因子的表达,参与慢性炎症反应和胰岛素抵抗过程,研究发现,血管生成素样蛋白2可影响冠状动脉局部血管的重建,促进动脉粥样硬化斑块内膜钙化的形成,对冠心病的发生发展其重要作用。现对血管生成素样蛋白2与冠心病的关系做一综述。     

血管生成素样蛋白2与心血管疾病的研究进展

血管生成素样蛋白2是近年来发现的一种分泌型糖蛋白,属于血管生成素样蛋白家族,主要由内脏脂肪细胞分泌,调节血管生成及各种抗炎、促炎因子的表达,参与慢性炎症反应和全身胰岛素抵抗过程,与代谢综合征及心血管疾病密切相关。现对血管生成素样蛋白2与心血管疾病的关系做一综述。     

血管生成素样蛋白4与代谢综合征的相关性探讨

目的探讨血管生成素样蛋白4(Angptl4)表达与代谢综合征的关系及在靶器官损害中的作用。方法选取查体健康者42例(对照组),代谢综合征患者48例(观察组);采用ELISA法检测两组患者血清Angptl4表达;分析Angptl4与代谢综合征相关指标的关系;采用高频超声检测两组颈动脉脉内膜—中层厚度(IMT)。结果与对照组比较,观察组血清Angptl4水平明显升高,P<0.001;相关性分析显示,Angptl4与腰围、空腹血糖、血压、甘油三酯、低密度脂蛋白胆固醇均呈正相关;多元线性回归结果显示,腰围增加、低密度脂蛋白胆固醇升高和甘油三酯升高是Angptl4表达增加的独立危险因素。观察组IMT明显高于对照组,P<0.05;多元线性回归结果显示,Angptl4表达增加、低密度脂蛋白胆固醇升高和空腹血糖增加是颈动脉IMT增厚的独立危险因素。结论血清Angptl4表达增加与代谢综合征的发生、发展密切相关,是代谢综合征患者早期动脉粥样硬化病变的重要参与因素。     

STEMI患者血管生成素样蛋白2的表达及替格瑞洛与氯吡格雷的影响

目的:探讨急性ST段抬高型心肌梗死(STEMI)患者血清血管生成素样蛋白2(Angptl 2)的表达及观察替格瑞洛与氯吡格雷两种抗血小板药对其浓度的影响。方法:入选同期入住我院心血管科患者40例为对照组,接受急诊PCI术的急性STEMI患者125例作为研究组,后者又随机分为替格瑞洛组(A组)50例(采用替格瑞洛联合阿司匹林治疗)和氯吡格雷组(B组)75例(采用氯吡格雷联合阿司匹林治疗),分别检测术前、术后24h、术后1周、术后1个月血清Angptl 2水平。结果:急性STEMI患者Angptl 2水平显著高于对照组(P0.05);入院时A、B两组Angptl 2水平无明显差异(P0.05),术后24h两组血清Angptl 2水平升高,但两组差异无统计学意义(P0.05),术后1周及术后1个月时A组较B组Angptl 2水平明显降低,差异有统计学意义(P0.05)。结论:Angptl 2可作为急性心肌梗死的重要风险预测指标,替格瑞洛较氯吡格雷更强的降低炎性因子Angptl 2的水平,提高动脉粥样硬化斑块的稳定性。     

血管生成素样蛋白2在2型糖尿病中的研究进展

血管生成素样蛋白2(ANGPTL2)是一种结构类似于血管生成素的分泌型循环糖蛋白,属于血管生成素样蛋白家族,其表达与肥胖症、胰岛素抵抗、2型糖尿病及其并发症等疾病密切相关。因此,ANGPTL2是糖尿病领域新的研究热点。本文就ANGPTL2的生物学特性、其在2型糖尿病及并发症中的研究进展进行综述。     

Cooperative interaction of Angiopoietin-like proteins 1 and 2 in zebrafish vascular development

Angiopoietin-like protein (Angptl) 1 and Angptl2, which are considered orphan ligands, are highly homologous, particularly in the fibrinogen-like domain containing the putative receptor binding site. This similarity suggests potentially cooperative functions between the two proteins. In this report, the function of Angptl1 and Angptl2 is analyzed by using morpholino antisense technology in zebrafish. Knockdown of both Angptl1 and Angptl2 produced severe vascular defects due to increased apoptosis of endothelial cells at the sprouting stage. In vitro studies showed that Angptl1 and Angptl2 have antiapoptotic activities through the phosphatidylinositol 3-kinase/Akt pathway, and coinjection of constitutively active Akt/protein kinase B mRNA rescued impaired vascular development seen in double knockdown embryos. These results provide a physiological demonstration of the cooperative interaction of Angptl1 and Angptl2 in endothelial cells through phosphatidylinositol 3-kinase/Akt mediated antiapoptotic activities.     

Angiopoietin-like 2, a circadian gene, improves type 2 diabetes through potentiation of insulin sensitivity in mice adipocytes

Angiopoietin-like (Angptl)2, a member of the Angptl protein family, is predominantly secreted from adipose tissue and the heart. Here, we demonstrate that the expression of Angptl2 in epididymal adipose tissue of C57BL/6J mice shows pulsatility and circadian rhythmicity and that the rhythmicity was disrupted in high-fat-fed and leptin receptor-deficient diabetic db/db mice with insulin resistance. To investigate whether the reduction in Angptl2 expression was related to the progression of diabetes, we treated db/db mice with recombinant Angptl2 for 4 wk during the peak period of Angptl2 expression in C57BL/6J mice. Angptl2-treated mice showed decreases in plasma glucose, insulin, triglyceride, and fatty acid levels and an increase in plasma adiponectin, a therapeutic regulator of insulin resistance, leading to improvements in glucose tolerance. In cultured adipocytes, recombinant Angptl2 increased adiponectin expression and stimulated insulin sensitivity partially by reducing the levels of tribbles homolog 3, a specific Akt kinase inhibitory protein. Conversely, Angptl2 small interfering RNA reduced adiponectin expression, resulting in insulin resistance. In preadipocytes, treatment with Angptl2 small interfering RNA inhibited differentiation to adipocytes and reduced adiponectin expression. Taken together, our results suggest that replenishment of Angptl2 stimulates insulin sensitivity and improves the type 2 diabetic state.     

Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism

Lipoprotein lipase (LPL) is a key regulator of triglyceride clearance. Its coordinated regulation during feeding and fasting is critical for maintaining lipid homeostasis and energy supply. Angiopoietin-like (Angptl)3 and Angptl4 are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angptl4- and Angptl3-deficient mice as well as transgenic mice overexpressing human Angptl4 in the liver. The Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma (PHP) LPL activity. A purified recombinant Angptl4 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angptl4-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angptl3-deficient mice also displayed hypotriglyceridemia with elevated PHP LPL activity, but these mice showed a greater effect in the fed state. Mice deficient in both Angptl proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angptl3 and Angptl4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.     

Angiopoietin-like protein 2 sensitively responds to weight reduction induced by lifestyle intervention on overweight Japanese men

Objective:

Overexpression of Angiopoietin-like protein 2 (Angptl2) in obese adipose tissues promotes adipose tissue inflammation and its-related metabolic abnormalities. In a comparative study with adiponectin, we investigated whether alterations in serum Angptl2 concentrations reflect the effect of lifestyle intervention on weight loss and improved metabolic parameters in overweight subjects.

Methods:

A total of 154 Japanese men (age, 40.9±5.1 years; body mass index, 26.9±3.6 kg m⁻²; abdominal circumference, 94.1±8.9 cm) underwent a 3-month lifestyle intervention and underwent follow-up for 3 months thereafter.

Results:

Decreased serum Angptl2 levels, but not increased serum adiponectin levels, were immediately apparent at the end of 3-month lifestyle intervention. Angptl2 levels continued to decrease for 3 months in parallel with body weight loss and improvement in metabolic indicators. In subjects showing ⩾6% weight reduction, markedly reduced Angptl2 levels were detected at the end of 3-month intervention, whereas increased adiponectin levels were detected 3 months after the end of intervention. Multivariate analysis revealed changes in serum Angptl2 levels associated with changes in triglycerides (TGs), aspartate aminotransferase and alanine aminotransferase. In contrast, changes in serum adiponectin levels were associated with altered high-density lipoprotein cholesterol (HDL-C) and fasting plasma glucose levels.

Conclusion:

A 3-month lifestyle intervention promoted weight reduction and improved glucose and lipid metabolism, an effect maintained 3 months later. Notably, our findings indicate that decreased Angptl2 levels are a good indicator of reduced visceral fat and metabolic improvement at early stages of lifestyle intervention. Thus, Angptl2 reflects adiposity and might be a key protein to regulate inflammation and TG metabolism, whereas adiponectin levels could reflect improved glucose and HDL-C metabolism.     

Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans

A previous study revealed that the difference in susceptibility to atherosclerotic lesions between inbred mouse strains SM/J and NZB/BlNJ was determined by one major locus (Ath8). In this study a (SM/J x NZB/BlNJ) F(1) x SM/J backcross localized Ath8 by quantitative trait locus mapping to chromosome 4 with a suggestive LOD score of 2.7. This quantitative trait locus (QTL) was confirmed using an (SM/J x NZB/BlNJ) intercross; Ath8 mapped to a 23cM region with a significant LOD score of 3.6. The genes for toll-like receptor 4 (T1r4), arachidonic acid epoxygenase (Cyp2j5), and angiopoietin-like protein 3 (Angptl3) map to this region. These candidate genes were analyzed for expression and sequence differences in the mouse and for associations with cardiovascular traits in human. Sequence analysis of Angptl3 shows a base pair substitution in SM, the susceptible strain, giving rise to an amino acid change in the fibrinogen homology domain of the protein. We found a significant association between ANGPTL3 and atherosclerotic lesions (P < 0.05) in human. These results suggest that Angptl3 is involved in atherosclerosis susceptibility in both mouse and human.     

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

We used gene knockout mice to explore the role of Angiopoietin-like-4 (Angptl4) in lipid metabolism as well as to generate anti-Angptl4 mAbs with pharmacological activity. Angptl4 -/- mice had lower triglyceride (TG) levels resulting both from increased very low-density lipoprotein (VLDL) clearance and decreased VLDL production and had modestly lower cholesterol levels. Also, both Angptl4 -/- suckling mice and adult mice fed a high-fat diet showed reduced viability associated with lipogranulomatous lesions of the intestines and their draining lymphatics and mesenteric lymph nodes. Treating C57BL/6J, ApoE -/-, LDLr -/-, and db/db mice with the anti-Angptl4 mAb 14D12 recapitulated the lipid and histopathologic phenotypes noted in Angptl4 -/- mice. This demonstrates that the knockout phenotype reflects not only the physiologic function of the Angptl4 gene but also predicts the pharmacologic consequences of Angptl4 protein inhibition with a neutralizing antibody in relevant models of human disease.