血凝素样氧化低密度脂蛋白受体1——新的药物作用靶点

血凝素样氧化低密度脂蛋白受体1(LOX-1)为最近发现的氧化修饰低密度脂蛋白(ox-LDL)受体,介导内皮细胞摄取代谢ox-LDL,以及ox-LDL对内皮细胞的损伤效应,引起内皮功能失调,导致动脉粥样硬化及相关心血管疾病的发生。适当阻断LOX-1与ox-LDL的结合,将会从源头上阻止ox-LDL对内皮细胞的损伤,从而保护血管功能,防止疾病的发生。所以,LOX-1可能是一个新的药物作用靶点。     

相关炎症因子与动脉粥样硬化

动脉粥样硬化(atherosclerosis,As)是一组主要累及全身大、中型弹力型动脉的血管硬化性疾病,以主动脉、冠状动脉和脑动脉多见,其特征是动脉内膜的脂质沉积和粥样斑块形成,且发病机制与高血压、血脂紊乱及血管内皮损伤等因素密切相关。近年来,各种细胞炎症因子与动脉粥样硬化的关系引起愈来愈多研究者的重视,现谨就择要作综述。     

Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells

BACKGROUND AND OBJECTIVES: Our previous studies have shown that oxidized low-density lipoprotein (ox-LDL) and angiotensin II (Ang II) influence each other's action in endothelial cells. This study was designed to examine the regulation by ox-LDL of the expression of angiotensin converting enzyme (ACE) gene in human coronary artery endothelial cells (HCAECs). In addition, we studied the effect of the HMG CoA reductase inhibitor simvastatin on this interaction. METHODS AND RESULTS: Cultured HCAECs were incubated with ox-LDL (10-80 microg/ml) for 1-24 h. Ox-LDL increased the expression of ACE in a concentration- and time-dependent fashion. The upregulation of ACE expression in response to ox-LDL was mediated by its endothelial receptor LOX-1, since pretreatment of HCAECs with a blocking antibody to LOX-1 prevented the expression of ACE (P<0.01). Native-LDL had no significant effect on ACE expression. In this process, ox-LDL-induced activation of mitogen-activated protein kinase (MAPK p42/44) played an important role, since pretreatment of HCAECs with the MAPK p42/44 inhibitor (PD98059, 10 microM) inhibited MAPK activation and subsequently attenuated the expression of ACE (P<0.01 vs. ox-LDL alone). In other experiments, we pretreated HCAECs with simvastatin (10 microM) and then exposed the cells to ox-LDL. Simvastatin markedly attenuated ox-LDL-induced MAPK activation, and concurrently reduced ACE expression (P<0.01 vs. ox-LDL alone). CONCLUSIONS: Our observations provide direct evidence that ox-LDL via LOX-1 activation induces ACE gene expression in HCAECs, and MAPK activation plays a signal transduction role in this process. Simvastatin, which inhibits MAPK activation, also blocks ox-LDL-mediated upregulation of ACE.     

Oxidized LDL,LOX-1 and Atherosclerosis

An elevated level of low density lipoprotein (LDL) cholesterol constitutes a major risk factor for genesis of atherosclerosis. Ox-LDL plays a more important role in the genesis and progression of atherosclerosis than the native LDL. Ox-LDL leads to endothelial dysfunction leading to expression of adhesion molecules and recruitment of monocyte in subendothelial space. Ox-LDL is taken up by macrophages via scavenger receptors, such as SR-A1, SR-A2 and LOX-1. Lately, LOX-1, a type II membrane protein receptor of ox-LDL, has gained much importance in relation to effects of ox-LDL on endothelial biology. Endothelial cells primarily express LOX-1 as receptor for ox-LDL and ox-LDL has been shown to upregulate expression of LOX-1. In addition, ox-LDL promotes the growth and migration of smooth muscle cells, monocytes/macrophages and fibroblasts. In this review we discuss the role of ox-LDL and LOX-1 in genesis and progression of atherosclerosis.     

Oxidized low-density lipoprotein and atherosclerosis implications in antioxidant therapy

Low-density lipoprotein (LDL)-cholesterol is important for cellular function, but in high concentrations, it can lead to atheroma formation. Over the past several decades, it has become abundantly evident that the oxidized form of LDL-cholesterol (ox-LDL) is more important in the genesis and progression of atherosclerosis than native unmodified LDL-cholesterol. Ox-LDL leads to endothelial dysfunction, an initial step in the formation of an atheroma. Ox-LDL acts via binding to a number of scavenger receptors (SR), such as SR-A1, SR-A2 and lectin-like oxidized low-density lipoprotein receptor (LOX-1). Ox-LDL can upregulate expression of its own receptor LOX-1 on endothelial cells and activate these cells. In addition, ox-LDL promotes the growth and migration of smooth muscle cells, monocytes/macrophages and fibroblasts. Ox-LDL also leads to the generation of reactive oxygen species that in physiologic concentrations combat invasion of the body by noxious agents, but when in excess, can lead to a state of oxidative stress. There is evidence for the presence of oxidative stress in a host of conditions such as atherosclerosis and aging. In this review, we discuss the role of oxidative stress, ox-LDL and LOX-1 in atherogenesis and the reasons why the traditional approaches to limit oxidant stress have not been successful.     

Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells

Oxidized low-density lipoprotein (ox-LDL) induces apoptosis in endothelial cells. However, steps leading to ox-LDL-induced apoptosis remain unclear. We examined the role of ox-LDL and its newly described receptor LOX-1 in the expression of intracellular pro- and antiapoptotic proteins and caspase pathways in human coronary artery endothelial cells (HCAECs). Cells were cultured and treated with different concentrations (10 to 80 microg/mL) of ox-LDL for different times (2 to 24 hours). Ox-LDL induced apoptosis in HCAECs in a concentration- and time-dependent manner. Ox-LDL also activated caspase-9 and caspase-3, but not caspase-8. After ox-LDL treatment, there was a significant release of activators of caspase-9, including cytochrome c and Smac from mitochondria to cytoplasmic compartment, and their release was not affected by treatment of cells with inhibitors of either caspase-8 or caspase-9. Ox-LDL also decreased expression of antiapoptotic proteins Bcl-2 and c-IAP (inhibitory apoptotic protein)-1, which are involved in the release of cytochrome c and Smac and activation of caspase-9, in a concentration- and time-dependent manner. On the other hand, ox-LDL did not change the expression of Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (FLIP) and proapoptotic protein Fas, which are required for the activation of caspase-8. Further, ox-LDL did not cause the truncation of Bid, which implies the activation of caspase-8. In other experiments, pretreatment of HCAECs with the caspase-9 inhibitor z-LEHD-fmk, but not the caspase-8 inhibitor z-IETD-fmk, blocked ox-LDL-induced activation of caspase-3 and apoptosis. As expected, pretreatment with the caspase-3 inhibitor DEVD-CHO inhibited ox-LDL-induced activation of caspase-3 and resultant apoptosis. The proapoptotic effects of ox-LDL were mediated by its receptor LOX-1, because pretreatment of HCAECs with antisense-LOX-1, but not sense-LOX-1, blocked these effects of ox-LDL. These findings suggest that ox-LDL through its receptor LOX-1 decreases the expression of antiapoptotic proteins Bcl-2 and c-IAP-1. This is followed by activation of apoptotic signaling pathway, involving release of cytochrome c and Smac and activation of caspase-9 and then caspase-3.     

高脂血症冠状动脉内皮损伤相关的微小RNA研究进展

目前认为冠状动脉血管内皮的损伤是冠状动脉粥样硬化形成的关键始动因素,氧化型低密度脂蛋白(ox-LDL)对内皮细胞的损伤机制一直都是研究的热点。新技术方法的开展使得微小RNA(miRNA)在ox-LDL所导致内皮细胞损伤过程中的作用被逐渐发现。本文简述了在高脂血症条件下涉及冠状动脉内皮细胞炎症、自噬、凋亡及功能障碍等内皮损伤作用的miRNAs。这些miRNA或许可为冠状动脉粥样硬化的预测、诊断甚至治疗提供新方向。     

Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders

LOX-1, a lectin-like 52-kD receptor for oxidized low-density lipoproteins (ox-LDL), is present primarily on endothelial cells. This receptor is upregulated by ox-LDL itself and by angiotensin II, endothelin, cytokines, and shear stress, all participants in atherosclerosis. This receptor is upregulated in the arteries of hypertensive, dyslipidemic, and diabetic animals. Upregulation of LOX-1 has been identified in atherosclerotic arteries of several animal species and humans, not only on the endothelial lining, but also in the neovasculature of the atherosclerotic plaque, and this receptor is often co-localized with apoptotic cells. Recent studies show upregulation of LOX-1 in the ischemic-reperfused myocardium. LOX-1 inhibition is associated with attenuation of atherosclerosis and associated ischemic injury. LOX-1 may be a novel, exciting target for drug therapy.     

LOX-1在动脉粥样硬化中的作用研究新进展

动脉粥样硬化(AS)是一种血管慢性炎症性病变,其中内皮细胞功能异常、单核细胞的黏附和迁移、平滑肌细胞的凋亡、泡沫细胞的形成和血小板的活化是AS形成的关键环节,最终结果是形成大、中动脉内膜下的粥样硬化斑块,造成管腔狭窄,远端组织器官供血不足甚至栓塞。低密度脂蛋白（LDL） 氧化形成的氧化型LDL（ox-LDL）在AS发生、发展过程中起着重要作用。目前在与AS发生、发展相关的细胞（如血管内皮细胞、血管平滑肌细胞、单核细胞、巨噬细胞以及泡沫细胞）上已经发现和鉴定了多种oxLDL受体,其中瘦素样氧化型低密度脂蛋白受体(LOX)-1表达于血管内皮细胞、巨噬细胞、血小板上,是ox-LDL的主要受体［1］,在AS的发生、发展中起着重要作用,本文将着重阐述近年来LOX-1影响AS发生发展相关效应与机制的新进展。     

氧化型低密度脂蛋白经血凝素样氧化型低密度脂蛋白受体1途径诱导血管内皮细胞损伤

探讨氧化型低密度脂蛋白致血管内皮细胞损伤的作用 ,并从血凝素样氧化型低密度脂蛋白受体 1的途径探讨损伤作用的机制。用1 2 5I标记的氧化型低密度脂蛋白进行放射性配基结合实验及配基竞争性抑制实验检测培养的人脐静脉内皮细胞中存在的特异性氧化型低密度脂蛋白受体 ,2 ,4 二硝基笨肼法测定乳酸脱氢酶活性 ,台盼兰染色、相差显微镜下观察细胞的形态学变化并计数细胞的存活率。结果发现 ,人脐静脉内皮细胞膜上存在与氧化型低密度脂蛋白高亲和力的结合位点 ,Scatchard分析Kd为 38.4± 18.8mg L、Bmax为 181.5± 5 5 .5ng 10 6 cells。氧化型低密度脂蛋白与人脐静脉内皮细胞作用 2 4h ,随着氧化型低密度脂蛋白剂量的增加 ,不仅显著增加人脐静脉内皮细胞释放乳酸脱氢酶的量 ,而且使人脐静脉内皮细胞的存活率下降 ,血凝素样氧化型低密度脂蛋白受体 1受体阻滞剂聚肌苷酸和爱兰苔胶可以阻断氧化型低密度脂蛋白的上述损伤作用。结果提示 ,血管内皮细胞表达氧化型低密度脂蛋白受体血凝素样氧化型低密度脂蛋白受体 1,氧化型低密度脂蛋白诱导对血管内皮细胞的损伤作用可能是通过血凝素样氧化型低密度脂蛋白受体 1的受体途径。     

EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules in human coronary artery endothelial cells via protein kinase B pathway

Uptake of oxidized low-density lipoprotein (ox-LDL) by endothelial cells is a critical step for the initiation and development of atherosclerosis. Adhesion molecules are inflammatory makers, which are upregulated by ox-LDL and play a pivotal role in atherogenesis. A number of studies suggest that fish and its constituents can reduce inflammation and decrease atherosclerosis. We hypothesized that fish oil constituents namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may reduce expression of adhesion molecules induced by ox-LDL. Cultured human coronary artery endothelial cells (HCAECs) were incubated with ox-LDL for 24 h. Parallel groups of cells were pretreated with DHA or EPA (10 or 50 microM) overnight before incubation with ox-LDL. Ox-LDL markedly increased the expression of P-selectin and intracellular adhesion molecule-1 (ICAM-1) (both protein and mRNA) in HCAECs, and enhanced the adhesion of monocytes to the cultured HCAECs. Both EPA and DHA decreased ox-LDL-induced upregulation of expression of P-selectin and ICAM-1, and the enhanced adhesion of monocytes to HCAECs. To determine the role of protein kinase B (PKB) as an intracellular-signaling pathway, HCAECs were treated with the PKB upstream inhibitor wortmannin (100 nM) or transfected with plasmids encoding dominant-negative mutants of PKB (PKB-DN) before treatment with DHA. Ox-LDL alone downregulated the activity of PKB; DHA attenuated this effect of ox-LDL, and both wortmannin and PKB-DN blocked the effect of DHA. The present study in human coronary endothelial cells suggests that both EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules, and the adhesion of monocytes to HCAECs by modulation of PKB activation. These effects may be important mechanisms of anti-atherosclerotic effects of fish and fish oils.     

8-iso-prostaglandin F(2alpha) increases expression of LOX-1 in JAR cells

Lectinlike oxidized LDL receptor-1 (LOX-1), a cell-surface receptor for oxidized LDL (ox-LDL), is proposed to be involved in endothelial dysfunction and in the pathogenesis of atherosclerosis. Preeclampsia is a pregnancy complication diagnosed by hypertension and proteinuria, characterized by endothelial dysfunction, and supposedly caused by compounds from hypoxic uteroplacental tissues. A feature of preeclampsia is formation of foam cells in maternal arterial walls of gestational tissue ("acute atherosis"). Oxidative stress is believed to play a role in the pathophysiology of preeclampsia. 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is a marker of oxidative stress in vivo, is biologically active in vitro, and is elevated in preeclamptic plasma and gestational tissue. In the present article, we hypothesized that 8-iso-PGF(2alpha) could induce the expression of LOX-1 in trophoblastic cells (JAR). We demonstrated augmented cellular uptake of (125)I-tyraminylcellobiose ox-LDL in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) versus control cells. Ligand blots revealed an increased binding of ox-LDL to LOX-1 in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L). Incubation with 8-iso-PGF(2alpha) (10 micromol/L) also resulted in augmented LOX-1 protein levels (Western blots) and mRNA levels (Northern blots). JAR cells transfected with 3 copies of a nuclear factor-kappaB binding site demonstrated dose-dependent activation of the reporter gene luciferase after incubation with 8-iso-PGF(2alpha) (0 to 10 micromol/L). We also demonstrated increased accumulation of neutral fats in JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) and ox-LDL compared with controls by oil red O staining. We speculate a potential role of isoprostanes and LOX-1 in preeclampsia in the development of "acute atherosis" of gestational spiral arteries.     

干扰Sestrin2表达对ox-LDL诱导的人脐静脉内皮细胞凋亡的影响

目的观察干扰Sestrin2表达对氧化型低密度脂蛋白(ox-LDL)诱导的人脐静脉内皮细胞(HUVEC)凋亡的影响。方法用ox-LDL处理HUVEC复制内皮细胞损伤模型。Western blot检测不同浓度ox-LDL处理HUVEC不同时间Sestrin2的蛋白表达水平及转染Sestrin2 siRNA后Sestrin2的蛋白表达水平;流式细胞术检测干扰Sestrin2表达后对ox-LDL诱导的HUVEC凋亡率的影响;Western blot检测干扰Sestrin2表达后对ox-LDL诱导的HUVEC中Caspase-3表达的影响及ox-LDL对HUVEC中JNK通路的影响。结果不同浓度(20、50和100 mg/L)的ox-LDL处理HUVEC 24 h均能明显上调Sestrin2表达;50 mg/L ox-LDL处理HUVEC不同时间(24 h和48 h)均能明显上调Sestrin2表达,24 h达高峰;转染Sestrin2 siRNA能明显抑制Sestrin2的表达;ox-LDL能明显诱导HUVEC凋亡,转染Sestrin2 siRNA能明显促进由ox-LDL诱导的HUVEC凋亡;ox-LDL能明显诱导p-JNK和p-c-Jun的表达,且SP600125能明显抑制由ox-LDL诱导的Sestrin2表达。结论 ox-LDL通过JNK/c-Jun信号通路诱导Sestrin2表达,干扰Sestrin2表达能明显促进ox-LDL诱导的HUVEC凋亡。     

Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors

A specific lectin-like endothelial receptor for oxidized low density lipoprotein (LOX-1), distinct from the scavenger receptor in monocytes/macrophages, has been identified and cloned. In this study, we examined the regulation of LOX-1 by oxidized low density lipoprotein (ox-LDL) and determined the role of LOX-1 in ox-LDL-induced apoptosis of cultured human coronary artery endothelial cells (HCAECs). Incubation of HCAECs with ox-LDL (40 microg/mL), but not native LDL, for 24 hours markedly increased LOX-1 expression (mRNA and protein). After 48 hours of preincubation of HCAECs with a specific antisense to LOX-1 mRNA (antisense LOX-1), ox-LDL-mediated upregulation of LOX-1 was suppressed (P<0.01). In contrast, treatment of HCAECs with sense LOX-1 had no effect. Ox-LDL also induced apoptosis (determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and DNA laddering) of HCAECs in a concentration- and time-dependent fashion. LOX-1 played an important role in ox-LDL-mediated apoptosis of HCAECs because antisense LOX-1 inhibited this effect of ox-LDL. Polyinosinic acid and carrageenan, 2 different chemical inhibitors of LOX-1, also decreased ox-LDL-mediated apoptosis of HCAECs. Nuclear factor (NF)-kappaB was markedly activated in ox-LDL-treated HCAECs. The critical role of NF-kappaB activation became evident in experiments with antisense LOX-1, which abolished ox-LDL-mediated NF-kappaB activation. In this process, an NF-kappaB inhibitor, caffeic acid phenethyl ester, also inhibited ox-LDL-mediated apoptosis of HCAECs. These findings indicate that ox-LDL upregulates its own endothelial receptor. Ox-LDL-induced apoptosis is mediated by the action of LOX-1. In this process, NF-kappaB activation may play an important role as a signal transduction mechanism.     

Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells

BACKGROUND: Aspirin is thought to exert salutary effects in vascular disease states by inhibiting platelet aggregation. Endothelial activation, accumulation of oxidized low-density lipoprotein (ox-LDL) and intense inflammation also characterize atherosclerotic plaque in acute myocardial ischemia. Ox-LDL induces expression of lectin-like receptors (LOX-1) on endothelial cells and leads to the expression of matrix metalloproteinases (MMPs), which destabilize the atherosclerotic plaque. We hypothesized that aspirin may interfere with LOX-1 expression and subsequent MMP activation. METHODS AND RESULTS: Cultured human coronary artery endothelial cells (HCAECs) were incubated with aspirin (1-5 mM), sodium salicylate (5 mM) or the cyclo-oxygenase inhibitor indomethacin (0.25 mM) before treatment with ox-LDL. Aspirin, in a dose- and time-dependent fashion, reduced ox-LDL-mediated LOX-1 expression (P<0.01). Ox-LDL also increased MMP-1 expression and activity, and treatment of HCAECs with aspirin decreased this effect (P<0.01). Ox-LDL also enhanced the activity of p38MAPK in HCAECs, and aspirin blocked this effect of ox-LDL (P<0.01). Treatment of HCAECs with salicylate, but not indomethacin, resulted in a suppression of LOX-1 expression, an effect similar to that of aspirin. Importantly, both aspirin and salicylate, but not indomethacin, decreased superoxide anion generation in ox-LDL-treated HCAECs (P<0.05). CONCLUSION: These observations suggest that aspirin inhibits ox-LDL-mediated LOX-1 expression and interferes with the effects of ox-LDL in intracellular signaling (p38MAPK activation) and subsequent MMP-1 activity. These novel effects of aspirin may complement its platelet inhibitory effect in acute myocardial ischemia.     

同型半胱氨酸对血管内皮细胞血凝素样氧化型低密度脂蛋白受体1 mRNA表达及氧化型低密度脂蛋白摄取的影响

为了研究同型半胱氨酸对血管内皮细胞血凝素样氧化型低密度脂蛋白受体1mRNA表达及对氧化型低密度脂蛋白摄取的影响，分别在培养的人脐静脉内皮细胞中加入不同浓度的同型半胱氨酸孵育48h后，利用逆转录-聚合酶链反应检测血凝素样氧化型低密度脂蛋白受体1mRNA表达的改变；采用放射配基法检测细胞对氧化型低密度脂蛋白的摄取。结果发现，随着同型半胱氨酸浓度的增加。提示同型半胱氨酸能促进脐静脉血管内皮细胞血凝素样氧化型低密度脂蛋白受体1mRNA的表达和对氧化型低密度脂蛋白的摄取，此效应可能与同型半胱氨酸致动脉粥样硬化作用有关。     

氧化低密度脂蛋白通过血凝素样氧化低密度脂蛋白受体1诱导血管内皮细胞粘附分子的表达

目的探讨血凝素样氧化低密度脂蛋白受体1（LOX-1）在氧化低密度脂蛋白（ox—LDL）诱导血管内皮细胞粘附分子表达中的作用。方法用不同浓度ox-LDL培养人脐静脉内皮细胞（HUVECs）,用RrealtimeRT—PCR测定LOX-1 mRNA的表达;RT—PCR测定细胞间粘附分子1（ICAM-1）、血管细胞粘附分子1（VCAM-1）以及E选择素的mRNA表达;用Westernblot测定LOX-1、ICAM-1、VCAM-1以及E选择素蛋白的表达,观察ox-LDL对血管内皮细胞粘附分子表达的影响。HUVECs预先用聚肌苷酸[poly（I）]和爱兰苔胶处理,再用ox—LDL培养,再分别测定上述粘附分子的表达水平,比较加入LOX-1阻断剂前后粘附分子表达的变化。结果ox-LDL各剂量组皆可上调LOX-1、ICAM-1、E选择素的mRNA和蛋白表达（P〈0．01）,在10～50μm/ml剂量范围内呈现明显的剂量一效应关系（P〈0．01）,但ox—LDL对VCAM-1的表达没影响。HUVECs预先与250μg／ml的poly（Ⅰ）或爱兰苔胶作用2h,然后加入50μg/ml的ox—LDL作用24h。poly（Ⅰ）和爱兰苔胶都能抑制ox—LDL诱导的LOX-1、ICAM-1和E选择素的mRNA和蛋白表达水平,与未阻断组相比,差异皆有统计学意义（P〈0．01）。结论ox—LDL可以上调血管内皮细胞粘附分子的表达,LOX-1受体阻断剂可以部分阻断ox—LDL的上调作用,ox-LDL诱导血管内皮细胞粘附分子的表过是通过LOX-1介导的。     

丝裂原活化蛋白激酶在动脉粥样硬化中作用的相关性研究

动脉粥样硬化(AS)是动脉的慢性炎性疾病。AS由炎症引发血管内皮细胞活化,包括释放细胞因子,粘附分子,基质金属蛋白酶和其它调节炎性介质(包括NO),导致血管内皮细胞功能紊乱和损伤,这是早期AS泡沫细胞形成的关键因素之一。丝裂原活化蛋白激酶(MAPKs)是调控炎症和抗炎反应重要的信号通路。激活的MAPKs,特别是ERK、JNK和p38 MAPKs,参与调节粘附分子和基质金属蛋白酶的表达。靶向给予ERK,JNK和p38 MAPKs信号通路抑制剂,其临床前研究数据表明它们有抗炎活性。因此,MAPKs的特异性抑制剂有望成为一种新的减轻动脉粥样化形成的治疗方法。     

沉默MAP4K4通过调控PPARγ/ABCA1通路缓解ox-LDL诱导的血管内皮细胞损伤

目的 探讨丝裂原活化蛋白激酶(MAP4K4)在氧化型低密度脂蛋白(ox-LDL)诱导的血管内皮细胞损伤中的作用及其机制.方法 采用100mg/Lox-LDL诱导人脐静脉内皮细胞(HUVEC)建立细胞损伤模型.RT-PCR检测HUVEC 中MAP4K4的mRNA表达水平.Western blot 法测定MAP4K4、Ba...