Nitric oxide selectively depletes macrophages in atherosclerotic plaques via induction of endoplasmic reticulum stress

BACKGROUND AND PURPOSE: Macrophages in atherosclerotic plaques have a tremendous impact on atherogenesis and plaque destabilization. We previously demonstrated that treatment of plaques in cholesterol-fed rabbits with the nitric oxide (NO) donor molsidomine preferentially eliminates macrophages, thereby favouring features of plaque stability. In this study, we investigated the underlying mechanism. EXPERIMENTAL APPROACH: Macrophages and smooth muscle cells (SMCs) were treated in vitro with the NO donors, spermine NONOate or S-nitroso-N-acetylpenicillamine (SNAP) as well as with the well-known endoplasmic reticulum (ER) stress inducers thapsigargin, tunicamycin, dithiothreitol or brefeldin A. Cell viability was analysed by Neutral Red viability assays. Cleavage of caspase-3, DNA fragmentation and ultrastructural changes were examined to characterize the type of macrophage death. Induction of ER stress was evaluated by measuring C/EBP homologous protein (CHOP) expression, phosphorylation of eukaryotic initiation factor 2 alpha (eIF2a), splicing of X-box binding protein 1 (XBP1) and inhibition of protein synthesis. KEY RESULTS: Macrophages and SMCs treated with spermine NONOate or SNAP showed several signs of ER stress, including upregulation of CHOP expression, hyperphosphorylation of eIF2 alpha, inhibition of de novo protein synthesis and splicing of XBP1 mRNA. These effects were similar in macrophages and SMCs, yet only macrophages underwent apoptosis. Plaques from molsidomine-treated atherosclerotic rabbits showed a 2.7-fold increase in CHOP expression as compared to placebo. Beside NO, selective induction of macrophage death could be initiated with thapsigargin and tunicamycin. CONCLUSIONS AND IMPLICATIONS: Induction of ER stress explains selective depletion of macrophages in atherosclerotic plaques by a NO donor, probably via inhibition of protein synthesis.     

Rosuvastatin restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice

BACKGROUND AND PURPOSE: Our goal was to elucidate mechanisms of the inhibitory effect of rosuvastatin on the accumulation of plaque oxidized low density lipoproteins (oxLDL) and on plaque volume, without lowering cholesterol, in mice with combined leptin and LDL-receptor deficiency (DKO). EXPERIMENTAL APPROACH: Twelve-week old DKO mice were treated with rosuvastatin (10 mg kg(-1) day(-1), s.c.) or placebo or no treatment for 12 weeks. The effect on blood variables, aortic plaque volume and composition and gene expression in the aorta and in THP-1 cells was assessed. KEY RESULTS: Rosuvastatin lowered free fatty acids (FFA), triglycerides, and increased insulin sensitivity, without affecting cholesterol. Rosuvastatin lowered the plaque volume, inhibited macrophage, lipid and oxLDL accumulation, and decreased the oxLDL-to-LDL ratio of plaques in the aortic arch. It increased superoxide dismutase 1 (SOD1), CD36, LXR-alpha, ABCA-1 and PPAR-gamma RNA expression in aortic extracts. SOD1 was the strongest inverse correlate of oxLDL. In THP-1 macrophages and foam cells, expression of SOD1 was lower than in THP-1 monocytes. Rosuvastatin restored expression of SOD1 in THP-1 macrophages and foam cells. CONCLUSIONS AND IMPLICATIONS: Rosuvastatin restored SOD1 expression in THP-1 macrophages and foam cells in vitro and in the aorta of DKO mice. The latter was associated with less oxLDL accumulation within atherosclerotic plaques and inhibition of plaque progression. This effect was obtained at a dose not affecting cholesterol levels but improving insulin sensitivity. SOD1 is a potentially important mediator of the prevention of oxLDL accumulation within atherosclerotic plaques.     

The influence of ezetimibe on classical and alternative activation pathways of monocytes/macrophages isolated from patients with hypercholesterolemia

Macrophages are crucial for the development of atherosclerotic plaques. Classically activated macrophages contribute to plaque growth and destabilization, while alternatively activated macrophages increase plaque stability. Here, we assessed the influence of ezetimibe on the activation of monocyte-derived macrophages isolated from patients with hypercholesterolemia (total cholesterol 263.4?±?12.5 mg/dl, low-density lipoprotein cholesterol 179.7?±?11.3 mg/dl, triglycerides 123.9?±?11.4 mg/dl). Cells were stimulated with 1 μg/ml lipopolysaccharide (LPS) or 1 μg/ml LPS plus 22 ng/ml ezetimibe. Control cells were left unstimulated. The expression of classical activation markers (interleukin-1β (IL-1β), nitric oxide (NO), and inducible nitric oxide synthase (iNOS)) and alternative activation markers (mannose receptor (MR) and arginase-1 (Arg1)) was determined after 48 h. The employed analytical methods included enzyme-linked immunosorbent assay, Griess reaction, real-time polymerase chain reaction, and Western blotting. LPS increased the secretion of IL-1β and NO and the expression of iNOS mRNA, iNOS protein, and Arg1 protein. It did not affect the expression of MR or Arg1 mRNA. In comparison to LPS stimulation, co-stimulation with ezetimibe decreased the secretion of IL-1β and the expression of iNOS mRNA and protein, while it increased MR mRNA and protein expression. Co-stimulation with ezetimibe did not change the secretion of NO or the expression of Arg1. The results suggest that ezetimibe in inflammatory in vitro conditions contributes to the suppression of classical and promotion of the alternative macrophage activation.     

Roles of 7-ketocholesterol on the Homeostasis of Intracellular Cholesterol Level

ABSTRACT:: Atherosclerotic plaque contains materials, such as cholesterol, oxysterols, cell debris, modified fatty acids, and infiltrated cells. Among them, cholesterol is the major component in plaque. Cholesterol is known to originate from the influx of extracellular materials, but this explanation is not enough for the cholesterol accumulation observed in atherosclerotic plaque. This study examined the origins of cholesterols in plaques. The main focus was to determine if the intracellular cholesterol levels are affected by oxysterols in human vascular smooth muscle cells. The results showed that the cholesterol levels increased in response to a 7-ketocholesterol (7K)-treatment in a dose-dependent manner. Eight enzymes involved in cholesterol biosynthesis were examined. Among them, squalene epoxidase (SQLE) was increased by 7K but not by 7α-hydroxycholesterol, 27-hydroxycholesterol (27OH-chol), or cholesterol. The 7K-induced SQLE expression was suppressed in the presence of the enzyme inhibitor SB203580 but not by UO126 and SP600125. The SQLE immunoreactivity was detected in the atherosclerotic plaque of the aortic roots from apoE mice. In addition, 7K increased the cholesterol level and SQLE expression in murine bone marrow-derived macrophages. This suggests that 7K increases the intracellular cholesterol level through an elevation of SQLE expression, which might affect the progress of cholesterol accumulation in the atherosclerotic lipid core.     

阿司匹林抑制兔腹主动脉粥样斑块破裂及MMP-2表达的研究

目的研究阿司匹林稳定粥样斑块的作用及其可能的作用机制。方法采用♂新西兰兔高脂饮食加腹主动脉内膜剥脱术制成高脂性动脉粥样硬化模型,然后给予阿司匹林5~20mg·kg-1治疗4wk,实验末诱发斑块破裂,运用图像分析方法测定斑块破裂处血栓形成的面积,利用光镜观察破裂斑块的形态学特征,采用免疫组化方法测定巨噬细胞的蛋白表达,原位杂交方法分别测定COX-2 mRNA和MMP-2 mRNA表达。结果阿司匹林5mg·kg-1和10mg·kg-1组可以抑制粥样斑块破裂处血栓的形成(P<0.01,P<0.05),且5mg·kg-1组的作用更明显;阿司匹林可以抑制斑块中泡沫细胞的形成和聚集,使纤维帽尤其是肩部区的结构保持得较为完整;阿司匹林5~10mg·kg-1可明显减少斑块内巨噬细胞数目(P<0.05),也能降低斑块中COX-2 mRNA的表达,且随着剂量的增加作用增强,在10~20mg·kg-1组的作用较为明显(P<0.05),还能明显降低粥样斑块中MMP-2 mRNA表达,但以阿司匹林5mg·kg-1组的作用较好(P<0.05)。结论阿司匹林可通过降低粥样斑块中MMP-2的表达增加动脉粥样斑块的稳定性。     

Regulation of smooth muscle cell growth, function and death in vitro by activated mast cells--a potential mechanism for the weakening and rupture of atherosclerotic plaques

The fibrous cap of a lipid-containing atherosclerotic plaque consists of collagen produced by arterial smooth muscle cells (SMCs) of synthetic phenotype. A thick cap protects the lipid-rich core, whereas a thin cap predisposes it to rupture, with ensuing acute clinical complications, such as myocardial infarction. Among the pathological mechanisms leading to plaque weakening and rupture, one possibility is loss of the matrix-synthesizing SMCs. Indeed, caps of ruptured coronary plaques contain a reduced number of SMCs. In contrast, in such lesions, the number of activated inflammatory cells, such as mast cells, is increased, suggesting that they may regulate the SMC number. We have shown that heparin proteoglycans secreted by activated mast cells can efficiently inhibit proliferation of SMCs in vitro and reduce their ability to produce collagen. Chymase, a neutral serine protease secreted by activated mast cells, can also inhibit SMC-mediated collagen synthesis by a transforming growth factor-beta-dependent and -independent mechanism, and moreover, cause degradation of the collagen matrix by activating latent interstitial collagenase (MMP-1). Furthermore, chymase can induce SMC apoptosis by degrading the extracellular matrix component fibronectin necessary for SMC adhesion, with subsequent disruption of focal adhesions and loss of outside-in survival signaling. Thus, activated mast cells may participate in the weakening and rupture of atherosclerotic plaques by secreting mediators, such as heparin proteoglycans and chymase, which affect the growth, function and death of arterial SMCs.     

Factors associated with apoptosis in symptomatic and asymptomatic carotid atherosclerotic plaques

The aim of this study was to investigate the differences that are present between apoptosis in symptomatic (with symptoms of cerebral ischemic attack) and asymptomatic carotid atherosclerotic plaques. The apoptotic process in macrophages and smooth muscle cells was evaluated. Cellular markers and products of immune cells in symptomatic and asymptomatic atherosclerotic plaque and endoarterectomy specimen were analyzed by immunohistochemistry. No statistically significant differences were present regarding the mean SMC actin-positive area. Using double staining of alpha-smooth muscle actin and TUNEL techniques, the number of smooth muscle cells in apoptosis was statistically higher in symptomatic plaque as compared with asymptomatic plaque. Statistically significant differences (p=0.009) were also found in the CD45-positive cells in the inflammatory infiltrate. The CD68-positive macrophages showed statistically significant differences (p=0.0001). Similarly, the double staining with CD68 and TUNEL revealed that apoptotic macrophages were mainly present in asymptomatic plaques rather than symptomatic plaques. Statistically significant differences (p<0.001) were found in the Bcl-2 expression, with higher values in asymptomatic plaques. Our data showed that the increase of the inflammatory cells contributes to plaque instability and that death due to apoptosis of smooth muscle cells in symptomatic plaques could contribute to their destabilization and explains their tendency to fracture.     

依达拉奉联合阿托伐他汀钙对老年血管性痴呆患者血液流变学及颈动脉硬化斑块的影响

目的 探讨依达拉奉联合阿托伐他汀钙对老年血管性痴呆患者血液流变学及颈动脉硬化斑块的影响.方法 选择2012年2月-2015年6月收治的老年血管性痴呆105例,根据治疗方法分为观察组55例和对照组50例,对照组采取依达拉奉治疗,观察组采用依达拉奉联合阿托伐他汀钙治疗.观察2组治疗前后简易智能状态量表(MMSE)、日常生活能力量表(ADL)、血脂水平、血液流变学、颈动脉硬化斑块大小变化情况.结果 治疗后,2组MMSE、一氧化氮(NO)水平较治疗前均明显上升,ADL评分、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、全血高低切黏度、血浆黏度、纤维蛋白原、颈动脉内膜中层厚度(IMT)及颈动脉粥样硬化斑块大小较治疗前下降(P＜0.05).观察组治疗后MMSE和血清血管内皮生长因子(VEGF)、NO水平高于对照组,ADL评分、TC、TG、LDL-C、全血高低切黏度、血浆黏度、纤维蛋白原、IMT、颈动脉粥样硬化斑块大小低于对照组(P＜0.05).2组均无严重不良反应.结论 依达拉奉联合阿托伐他汀钙治疗老年血管性痴呆,具有较好的调脂作用,还能改善患者血液流变学指标及血管内皮细胞功能,促进颈动脉硬化斑块缩小,有利于患者认知障碍及日常生活能力改善.     

Heme oxygenase-1 inhibits progression and destabilization of vulnerable plaques in a rabbit model of atherosclerosis

Although heme oxygenase-1 (HO-1) has been implicated in protection against atherogenesis, its role in vulnerable plaques remains to be fully elucidated. This study was aimed to explore the effect of HO-1 on the progression and stabilization of vulnerable plaques and the possible mechanism. We established a vulnerable plaque model by local transfection with recombinant p53 adenovirus to plaques in rabbits fed a high-cholesterol diet. HO-1 activity was modulated by intraperitoneal injection of hemin or Sn-protoporphyrin IX (SnPP). HO-1 induction by hemin inhibited the progression of atherosclerotic lesions and changed the plaque morphology and composition into a more stable phenotype. In addition, hemin treatment is associated with a reduction in matrix metalloproteinase-9, interleukin-6 and tumor necrosis factor-α production, an increase in interleukin-10 level, as well as a decrease of TUNEL labeled apoptosis of smooth muscle cells in lesions. Compared with the control group, aortic nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) activity decreased markedly, whereas endothelial nitric oxide synthase (eNOS) activity increased significantly in the Hemin group. In contrast, inhibition of HO-1 by SnPP induced reversed effects and augmented plaque progression and vulnerability. After pharmacological triggering, the incidence of plaque disruption in SnPP group was significantly higher than that in control group (79% vs. 33%, P<0.05), while no plaque in Hemin group developed disruption (0% vs. 33%, P<0.05). These findings suggest that HO-1 induction could delay progression and enhance stability of atherosclerotic plaques, possibly through the attenuation of plaque inflammation and apoptosis, and the suppression of iNOS/NO production.     

Early atherosclerosis is accompanied by a decreased rather than an increased accumulation of fatty acid hydroxyderivatives.

The content of 13-hydroxylinoleic acid (13-HODE) and 15-hydroxyarachidonic acid (15-HETE) in the rabbit thoracic aorta was measured using high performance liquid chromatography after chronic exposure to cholesterol and a high dose of molsidomine, a donor of nitric oxide (NO). Cholesterol-induced fatty streak formation was accompanied by a decrease in the amounts of esterified 13-HODE and 15-HETE. The reduction of the esterified 13-HODE content correlated significantly with the severity of the lesions. These results do not support the hypothesis that fatty acid hydroperoxides accumulate in the arterial wall during atherosclerosis. On the other hand, the quantity of esterified 13-HODE and 15-HETE was increased markedly after exposure to molsidomine. The high dose of this agent could have initiated radical reactions (via liberation of NO and production of superoxide anions) thereby leading to a raise of the 13-HODE and 15-HETE content of the vessel.     

Simvastatin reduces serum level of vascular endothelial growth factor in hypercholesterolemic patients

Vascular endothelial growth factor plays a pivotal role in the progression of atherosclerotic lesions and causes instability of atherosclerotic plaques by inducing neoangiogenesis inside the current plaque. The pro-inflammatory cytokine interleukin (IL-) 6 induces vascular endothelial growth factor in smooth muscle cells (SMC). HMG-CoA reductase inhibitors (statins), display beside their lipid-lowering potency various pleiotropic effects. Such pleiotropic effects include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques. In this study we investigate the influence of statin treatment on the serum levels of VEGF in hypercholesterolemic patients. One hundred and seven hypercholesterolemic patients were treated with 20 (n = 52) or 40 mg (n = 55) simvastatin daily. Six weeks of treatment resulted in a significant decrease of VEGF from 1017.1 +/- 297.8 pg/mL at baseline to 543.5 +/- 317.4 pg/mL after 6 weeks (-47.7%) and to 211.8 +/- 155.3 pg/mL after 6 months (-79.7%; all P < 0.001). IL-6 induced the expression of vascular endothelial growth factor in human SMC as analyzed by rt-PCR and flow cytometry. Statins decreased the stimulatory effect of IL-6 on mRNA and protein levels. This effect could be inhibited by co-incubation with mevalonate acid. This study contributes in understanding the pleiotropic effects of statins particularly with regard to their use in treatment and prevention of cardiovascular disease.     

7-Ketocholesterol and cholesterol-5α,6α-epoxide induce smooth muscle cell migration and proliferation through the epidermal growth factor receptor/phosphoinositide 3-kinase/Akt signaling pathways

Oxysterols, the major components of oxidized low-density lipoproteins (ox-LDLs), are present in atherosclerotic plaque and are suggested to play an active role in plaque development. The formation of an atherosclerotic lesion occurs through activation of cellular events that include vascular smooth muscle cell (SMC) migration and proliferation. Therefore, we investigated the roles of two common oxysterols, 7-ketocholesterol (7-keto) and cholesterol-5α,6α-epoxide (α-epoxide) on SMCs. Our results showed that 7-keto and α-epoxide promoted SMC migration by a chemotactic assay, and induced mitogenic effects by MTT assay and BrdU assay. Specific inhibitors confirmed that MMPs, EGFR and PI3K are involved in oxysterol-induced SMC migration, while EGFR, ERK, Akt, and sphingomyelin/ceramide pathways might play a role in SMC proliferation. More, the co-immunoprecipitation study indicated that 7-keto and α-epoxide caused EGFR phosphorylation and there was an interaction between EGFR and PI3K. At protein expression level, Akt and ERK were activated, at messenger RNA level, MMP-2/9 mRNA was transcribed, at enzyme activity level, the MMP-2/9 enzyme activity were increased in SMCs treated with 7-keto and α-epoxide according to Western bolt, RT-PCR and a fluorogenic substrate. Taken together, we concluded that 7-keto and α-epoxide may be an atherogenic factor by stimulating SMC migration and proliferation.     

Therapeutic strategies to deplete macrophages in atherosclerotic plaques

Macrophages can be found in all stages of atherosclerosis and are major contributors of atherosclerotic plaque development, progression and destabilization. Continuous recruitment of monocytes drives this chronic inflammatory disease, which can be intervened by several strategies: reducing the inflammatory stimulus by lowering circulating lipids and promoting cholesterol efflux from plaque, direct and indirect targeting of adhesion molecules and chemokines involved in monocyte adhesion and transmigration and inducing macrophage death in atherosclerotic plaques in combination with anti-inflammatory drugs. This review discusses the outlined strategies to deplete macrophages from atherosclerotic plaques to promote plaque stabilization.     

Matrix metalloproteinases: a potential therapeutic target in atherosclerosis

Mature human atherosclerotic plaques are frequently characterized by a lipid-rich core covered by a fibrous cap composed of fibrillar collagens, elastin, proteoglycans and smooth muscle cells (SMC). Most sudden deaths due to acute myocardial infarction are caused by rupture of coronary atheroma, leading to a prothrombotic response followed by rapid occlusion of the artery. The accumulation of macrophage-derived foam cells in vulnerable shoulder regions of atherosclerotic plaques correlates with increased local release of matrix-degrading metalloproteinases (MMPs) and weak fibrous cap tissue. These findings suggest a potential role of macrophage-derived MMPs in the weakening and ultimate rupture of plaque structures. Consequently, several studies have focussed on the hypothesis that inhibiting MMP activity would reduce plaque volume and prevent plaque rupture and therefore would be useful in the treatment of atherosclerosis. However, current synthetic MMP inhibitors are not very specific and clinical results have so far been inconclusive. The development of selective inhibitors and focal gene transfer approaches may be better suited for the treatment of atherosclerosis.     

Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture

Atherosclerosis is still an important disease. It accounts for 39% of deaths in the U.K. and 12 million U.S citizens have atherosclerosis-associated disease. Atherosclerosis may exert clinical effects by slow narrowing, producing stable angina or dramatic rupture, producing acute coronary syndromes such as unstable angina or myocardial infarction and death. Macrophages are abundant in ruptured atherosclerotic plaques. Macrophages are innate immune effectors, i.e. they are activated without antigenic specificity. This may make them liable to indiscriminate tissue damage, since they are less selective than lymphocytes. Macrophages are recruited and activated by many signals and have an impressive armamentarium of molecules to promote tissue damage. Macrophage recruitment by abnormal endothelium over developing atherosclerotic plaques, is aided by endothelial expression of adhesion molecules (ICAM-1, VCAM, ELAM). Use of knockout mice has implicated the chemoattractant cytokine (chemokine) MCP-1 in attracting macrophage recruitment in atherosclerosis. Macrophage-activation stimuli associated with atherosclerotic risk factors include oxidised low density lipoprotein (oxLDL, "bad cholesterol"), advanced glycosylation end products (AGEs) of diabetes, angiotensin II and endothelin. Substantial work has clarified macrophage activation by OxLDL via macrophage scavenger receptors (MSRs), especially MSRA and CD36. Activated macrophages express effector molecules that kill cells and degrade extracellular matrix. These include Fas-L and nitric oxide (NO). Macrophage NO is derived from the high output inducible nitric oxide synthase (iNOS) pathway and upregulates vascular smooth muscle (VSMC) cell surface Fas, priming them for apoptosis. Activated macrophages express surface Fas-L, similar to cytotoxic T-lymphocytes and natural killer cells. Since VSMCs promote plaque stability, VSMC apoptosis may promote plaque rupture. Macrophages express multiple metalloproteinases (e.g. stromelysin) and serine proteases (e.g. urokinase) that degrade the extracellular matrix, weakening the plaque and making it rupture prone. Macrophages secrete numerous other effectors including reactive oxygen species, eicosanoids, tumour necrosis factor alpha and interleukin-1. Macrophage-derived transforming growth factor beta promotes fibrosis. Existing cardiovascular treatments including angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, aspirin, cholesterol reduction agents especially statins may inhibit macrophages. The interaction of NO-donors with macrophages and apoptosis is complex and bifunctional. Traditional anti-inflammatory agents such as glucocorticoids and cyclophosphamide have very serious side effects and are probably inappropriate. Novel anti-inflammatory agents e.g. new immunosuppressives and anti-TNF therapy may have an improved cost-benefit ratio.     

基质金属蛋白酶在动脉粥样硬化斑块中的表达

目的探讨基质金属蛋白酶对动脉硬化斑块稳定性的影响。方法选择人股动脉动脉粥样硬化（AS）斑块标本40个,以脂核面积占斑块面积40％为标准设立不稳定斑块（UP）组和稳定斑块（SP）组,冰冻切片进行免疫组织化学染色,观察基质金属蛋白酶-2（MMP-2）、基质金属蛋白酶-9（MMP-9）的分布特点。结果HE染色见UP组标本脂核面积大,纤维帽薄弱,斑块内可见大量的泡沫细胞和巨噬细胞,局部常见内膜损伤。MMP-2、MMP-9在UP组表达高于SP组,在UP组肩部表达最高[分别为（18．71±7．64）、（18．53±2．34）A]。结论肩部是不稳定AS斑块易损部位,基质金属蛋白酶参与AS斑块失稳定过程。     

Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice

Angiotensin (Ang) II contributes to the development of atherosclerosis, while Ang-(1–7) has atheroprotective actions. Accordingly, angiotensin-converting enzyme 2 (ACE2), which breaks-down Ang II and forms Ang-(1–7), has been suggested as a target against atherosclerosis. Here we investigated the actions of diminazene, a recently developed ACE2 activator compound, in a model of vulnerable atherosclerotic plaque. Atherosclerotic plaque formation was induced in the carotid artery of ApoE-deficient mice by a shear stress (SS) modifier device. The animals were treated with diminazene (15 mg/kg/day) or vehicle. ACE2 was strongly expressed in the aortic root and low SS-induced carotid plaques, but poorly expressed in the oscillatory SS-induced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorated the composition of aortic root and low SS-induced carotid plaques by increasing collagen content and decreasing both MMP-9 expression and macrophage infiltration. Interestingly, these beneficial effects were not observed in the oscillatory SS-induced plaque. Additionally, diminazene treatment decreased intraplaque ICAM-1 and VCAM-1 expression, circulating cytokine and chemokine levels and serum triglycerides. In summary, ACE2 was distinctively expressed in atherosclerotic plaques, which depends on the local pattern of shear stress. Moreover, diminazene treatment enhances the stability of atherosclerotic plaques.     

瑞舒伐他汀钙对高龄冠心病患者颈动脉粥样硬化斑块的影响

目的探讨瑞舒伐他汀钙对高龄患有冠状动脉粥样硬化性心脏病患者合并颈动脉粥样硬化斑块的作用。方法 58例高龄冠状动脉粥样硬化性心脏病合并颈动脉粥样硬化的患者给予口服瑞舒伐他汀钙10mg/次,1次/d,治疗1年,分别监测治疗前和治疗3、6、9个月及1年时总胆固醇(TC)含量、三酰甘油(TG)浓度、低密度脂蛋白-胆固醇(LDL-C)含量以及高密度脂蛋白-胆固醇(HDL-C)含量的水平和颈动脉内膜中层厚度(IMT),并推算颈动粥样硬化斑块的积分值。结果与治疗前比较,治疗3个月时血清中TC、TG、LDL-C的浓度水平降低(P<0.05),血清中HDL-C的浓度水平增高(P<0.05);治疗6、9个月及1年时,TC、TG及LDL-C水平显著降低(P<0.01),HDL-C水平显著增加(P<0.01);颈动脉粥样硬化斑块积分与IMT药物治疗1年时差异有统计学意义(P<0.05)。结论瑞舒伐他汀钙能明显改善冠心病患者血清中血脂的浓度,还能稳定及逐渐减少动脉粥样硬化斑块。