内皮型、诱导型一氧化氮合酶在乳腺癌中的表达

目的 :研究内皮型一氧化氮合酶 (eNOS)、诱导型一氧化氮合酶 (iNOS)在乳癌中表达及与淋巴结转移的关系。方法 :采用免疫组化S P法检测 60例乳癌中eNOS和iNOS的表达。结果 :eNOS和iNOS阳性在乳癌中表达率分别为 75 0 %和71 7%。在淋巴结转移组和无淋巴结转移组中eNOS阳性表达率分别为 66 7%和 83 3 % ,两组间差异无统计学意义 (χ2 =2 2 2 ,P >0 0 5) ,而iNOS在淋巴结转移和无转移组中阳性表达率分别为 53 3 %和 90 0 % ,两组间差异有统计学意义 (χ2 =9 93 ,P <0 0 1 )。结论 :内皮型、诱导型一氧化氮合酶在乳腺癌中高表达 ;iNOS的表达与乳腺癌的淋巴转移相关     

地尔硫(艹卓)对肺动脉高压大鼠血红素氧合酶1和一氧化氮合酶的影响

目的 :　探讨钙离子拮抗剂地尔硫 艹卓(商品名合心爽 )对大鼠缺氧性肺动脉高压模型肺小动脉 (SPA)血红素氧合酶 (HO) - 1、一氧化氮合酶 (NOS)表达的影响。方法 :常压缺氧 [(10 %± 1% )O2 ]6周复制大鼠肺动脉高压模型。缺氧 2周后随机分为模型组和地尔硫 艹卓 治疗组。检测右室收缩压 (RVSP)、右心肥大指数 (RVHI) ,用光镜和透射电镜观察肺的病理改变 ,并进行形态学定量。用免疫组化和Westernblot法观察肺内HO - 1、内皮型和诱生型NOS(eNOS和iNOS)的表达和分布。放免法检测肺组织环 -磷酸鸟苷 (cGMP)含量。结果 :地尔硫 艹卓 明显降低缺氧大鼠的RVSP和RVHI,减轻肺小动脉中膜肥厚 ,促进eNOS及抑制iNOS表达 ,但对缺氧引起的HO - 1表达增高和内皮超微结构损伤无显著影响。结论 :地尔硫 艹卓 能明显减轻肺动脉高压性结构重塑 ,这种作用可能部分通过抑制iNOS、促进eNOS ,而不减少HO - 1的表达等环节来实现。     

Expression of haem oxygenase in cirrhotic rat liver

The haem oxygenase (HO)/carbon monoxide (CO) system has been implicated as a modulator of hepatobiliary function. This study investigated HO expression in the process of cirrhosis development, as well as its relationship to nitric oxide synthase (NOS). Liver cirrhosis was induced in rats by chronic bile duct ligation (BDL). HO mRNA expression was evaluated by competitive RT-PCR, while protein expression was determined by immunoblotting and immunohistochemistry. In liver tissue where cirrhosis had fully developed, the expression levels of HO-1 were greatly enhanced at both mRNA and protein level compared with sham livers. Immunohistochemistry showed that HO-1 was induced in hepatocytes and enhanced in some of the Kupffer-like cells in BDL livers. In contrast, there was no difference between the sham and the BDL livers for the expression levels of HO-2. Interestingly, administration of the NOS inhibitor aminoguanidine (AG) or N(G)-nitro-L-arginine methyl ester inhibited HO-1 expression. To study further the role of HO-1 in the development of liver cirrhosis, hepatocytes were isolated from the rats at different time points after BDL operation. HO-1 was expressed in hepatocytes at high levels during the early onset of cirrhosis but dropped slightly at a later stage of cirrhosis. Zinc protoporphyrin IX (ZnPP), an HO inhibitor, blocked HO-1 expression in hepatocytes from BDL cirrhotic rats, but enhanced the activity of inducible NOS (iNOS) in BDL hepatocytes. In conclusion, HO-1 was induced in the hepatocytes of rats undergoing cirrhosis, suggesting that HO-1 plays a role in the development of liver cirrhosis. Induction of HO-1 may be mediated partially by iNOS. However, once it is induced, HO-1 may be important in modulating iNOS activity, thus playing a protective role in liver cirrhosis.     

Endothelial nitric oxide synthase is a critical factor in experimental liver fibrosis

Reduced expression of endothelial nitric oxide synthase (eNOS) in chronic liver disease can reduce hepatic perfusion and accelerate fibrosis. The relationship between eNOS expression and liver fibrogenesis remains unclear. We investigated whether l -arginine attenuated chronic liver fibrosis through eNOS expression. Chronic liver injury was induced by administration of carbon tetrachloride (CCl₄) to mice for 8 weeks. 5-Methylisothiourea hemisulphate (SMT), an iNOS inhibitor, or l -arginine, a NOS substrate were injected subcutaneously. CCl₄-induced hepatotoxicity, oxidative stress and accumulation of collagen were detected in the liver. The expression levels of inducible NOS (iNOS) and nuclear factor kappa-B (NF-κB) activity in the liver after CCl₄ treatment were increased but eNOS expression and activator protein-1 (AP-1) activity were decreased. Both SMT and l -arginine effectively reduced CCl₄ induced oxidative stress and collagen formation, but l -arginine showed a significantly greater suppression of collagen formation, iNOS expression and NF-κB activity. l -Arginine also restored the level of eNOS and AP-1 activity. l -Arginine was more effective than SMT in suppressing liver fibrosis. l -Arginine might improve NO production which facilitates hepatic blood flow and thus retards liver fibrogenesis. Our results showed that the reduced eNOS expression in CCl₄-treated mice was reversed by l -arginine. Furthermore, l -arginine also reversed the reduced AP-1 activity, an eNOS promoter.     

Expression of inducible nitric oxide synthase and nitrotyrosineduring the evolution of experimental pulmonary tuberculosis

Nitric oxide (NO) is a relevant antimycobacterial factor in mouse macrophages. NO is a product of inducible nitric oxide synthase (iNOS). NO toxicity is greatly enhanced by reacting with superoxide to form peroxynitrite that reacts with many biological molecules. Tyrosine is one of the molecules with which NO reacts and the product is nitrotyrosine (NT). The production of peroxynitrite and the nitrosylation of proteins might play a role in bacterial killing and also in mediating host injury. In this study, we used a well-characterized mouse model of pulmonary tuberculosis to examine the local kinetics of expression and cellular distribution of iNOS and NT at the cellular and subcellular level. The histopathological study showed two phases of the disease: early and late. The early phase was characterized by mononuclear inflammation and granuloma formation. During this phase, high percentages of activated macrophages were observed that were immunostained for iNOS and NT. Immuno-electronmicroscopy showed NT immunoreactivity in lysosomes and mycobacterial wall and cytoplasm. The concentration of iNOS mRNA and NO metabolites were also elevated. The late phase was characterized by progressive pneumonia with focal necrosis and a decrease of iNOS mRNA and NO metabolites. The strongest NT immunostained areas were the necrotic tissue. Macrophages became foamy cells with scarce iNOS immunostaining but strong NT immunoreactivity. At the ultrastructural level, these cells showed NT immunolabeling in cytoskeleton, mitochondria, lysosomes and cell membrane. NT was also located in bronchial epithelial cell mitochondria, in cell membranes and cytoplasm of endothelial cells and in actin bundles within smooth muscle cells. These results suggest an important role of NO in mycobacterial killing, particularly during the early phase of the infection. They also suggest an important participation by NO in tissue damage during the late phase of the disease.     

Opposite effect of oxidative stress on inducible nitric oxide synthase and haem oxygenase-1 expression in intestinal inflammation: anti-inflammatory effect of carbon monoxide

Inducible nitric oxide synthase (iNOS) is expressed in intestinal epithelial cells (IEC) of patients with active inflammatory bowel disease (IBD) and in IEC of endotoxaemic rats. The induction of iNOS in IEC is an element of the NF-kappaB-mediated survival pathway. Haem oxygenase-1 (HO-1) is an AP-1-regulated gene that is induced by oxidative stress. The enzyme produces carbon monoxide (CO), which may attenuate the inflammatory response. The aim of this study was to investigate the regulation and interaction of iNOS and HO-1 in response to inflammation and oxidative stress. Male Wistar rats were treated with the thiol-modifying agent diethylmaleate (DEM) to induce oxidative stress and rendered endotoxaemic by LPS injection. Human colonic biopsies and the human colon carcinoma cell line DLD-1 were treated with DEM and the lipid peroxidation end-product 4-hydroxynonenal to induce oxidative stress and exposed to cytokine mix (CM) to mimic inflammation. In some experiments, cells were incubated with 250-400 ppm CO prior to and during stimulation with CM. HO-1 and iNOS expression was evaluated by RT-PCR, western blotting, and immunohistology. NF-kappaB activation was evaluated by EMSA. LPS induced iNOS but not HO-1 in epithelial cells of the ileum and colon. Oxidative stress strongly induced HO-1 in epithelial and inflammatory cells. Combined oxidative stress and endotoxaemia decreased iNOS expression but strongly induced HO-1 expression. Similarly, CM induced iNOS but not HO-1 in colonic biopsies and DLD-1 cells. Oxidative stress prevented iNOS induction in an NF-kappaB-dependent manner but increased HO-1 expression in CM-exposed DLD-1 cells. CO inhibited iNOS mRNA induction in CM-stimulated DLD-1 cells. These data demonstrate opposite regulation of iNOS and HO-1 in intestinal epithelial cells in response to cytokine exposure and oxidative stress. These findings suggest that iNOS (NF-kappaB driven) and HO-1 (AP-1 driven) represent mutually exclusive survival mechanisms in intestinal epithelial cells.     

High nitric oxide production,secondary to inducible nitric oxide synthase expression,is essential for regulation of the tumour‐initiating properties of colon cancer stem cells

Chronic inflammation is a leading cause of neoplastic transformation in many human cancers and especially in colon cancer (CC), in part due to tumour promotion by nitric oxide (NO) generated at inflammatory sites. It has also been suggested that high NO synthesis, secondary to inducible NO synthase (iNOS) expression, is a distinctive feature of cancer stem cells (CSCs), a small subset of tumour cells with self‐renewal capacity. In this study we explored the contribution of NO to the development of colon CSC features and evaluated potential strategies to treat CC by modulating NO production. Our data show an integral role for endogenous NO and iNOS activity in the biology of colon CSCs. Indeed, colon CSCs with high endogenous NO production (NO^high) displayed higher tumourigenic abilities than NO^low fractions. The blockade of endogenous NO availability, using either a specific iNOS inhibitor or a genetic knock‐down of iNOS, resulted in a significant reduction of colon CSC tumourigenic capacities in vitro and in vivo. Interestingly, analysis of genes altered by iNOS‐directed shRNA showed that the knockdown of iNOS expression was associated with a significant down‐regulation of signalling pathways involved in stemness and tumour progression in colon CSCs. These findings confirm that endogenous NO plays an important role in defining the stemness properties of colon CSCs through cross‐regulation of several cellular signalling pathways. This discovery could shed light on the mechanisms by which NO induces the growth and invasiveness of CC, providing new insights into the link between inflammation and colon tumourigenesis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Endothelial nitric oxide synthase gene polymorphisms and prostate cancer risk in Serbian population

Genome-wide association studies (GWAS) have identified over 46 SNPs associated with human prostate cancer (PCa). Some studies have shown correlation of the nitric oxide synthase (NOS) NOS3 gene polymorphisms with the risk and/or progression of PCa. This study aimed to evaluate the association of NOS3 gene polymorphisms (−786T>C, −764A>G, −714G>T, −690C>T, −649G>A and 894G>T) with PCa risk and progression. 150 patients with PCa, 150 patients with BPH and 100 age-matched healthy controls were recruited in this study. Genotyping of promoter polymorphisms was performed by bi-directional DNA sequencing, and for 894G>T by RFLP analysis. There was no significant association between the alleles and genotypes of these genetic variants and PCa risk. For −786T>C polymorphism, we found that C allele is associated with absence of metastases, assuming dominant genetic model (P = 0.049; OR, 0.50; 95% CI, 0.25–1.00). It was found that, compared with NOS3 −690C>T variant CC genotype, CT and TT genotypes confer decreased risk of developing metastases (dominant model, P = 0.015, OR, 0.24; 95% CI, 0.07–0.88) and show association with low clinical tumour stage, compared with stages T₃ and T₄ (dominant model, P = 0.046, OR, 0.20; 95% CI, 0.04–1.02). Genetic variants −764A>G, −714G>T, −649G>A were not detected in our study group. There is evidence of an inverse correlation of the NOS3 894G>T minor allele with high serum PSA (>20 ng/ml) (dominant model, P = 0.013, OR, 0.37; 95% CI, 0.17–0.82). Our results suggest that NOS3 gene polymorphisms are genetic susceptibility factors for the progression of PCa and patient outcome.     

Immunohistochemical localization of inducible and endothelial constitutive nitric oxide synthase in neoplastic and autoimmune thyroid disorders

AIM: To investigate the distribution of nitric oxide synthase in tissues derived from patients with autoimmune or neoplastic disorders of the thyroid gland in order to test whether the expression of inducible nitric oxide synthase or endothelial constitutive nitric oxide synthase (two subtypes of EC 1.14.13.39) may be related to the inflammatory activity or degree of neoplasia. EXPERIMENTAL DESIGN: The expression of nitric oxide synthases was examined by immunohistochemistry in tissues from patients with either Hashimoto's thyroiditis (n=6), hyperplastic glands (Graves' disease) (n=7), adenomas (n=8), multinodular goitres (n=7), papillary carcinomas (n=4) or follicular carcinomas (n=5). RESULTS: Expression of inducible nitric oxide synthase was found in 22 of the tissues and was not specific for any of the examined thyroid disorders. Expression of endothelial constitutive nitric oxide synthase was found in some of the epithelial cells in all the tissues. There was no correlation between the intensity and distribution of the immunostaining and the thyroid disorders. CONCLUSION: Demonstration of nitric oxide synthase cannot be used for diagnostic purposes. The expression of endothelial constitutive nitric oxide synthase in all tissues indicates that the enzyme may be of importance for the function or growth of the thyroid epithelial cells.     

Activation of endothelial nitric oxide synthase following spinal cord injury in mice

Endothelial nitric oxide synthase (eNOS) plays a neuroprotective role after cerebral ischemia through the production of NO, which enhances cerebral blood flow. However, precise details regarding activation of eNOS after spinal cord injury (SCI) largely remain to be elucidated. In the present study we investigated chronological alteration and cellular location of eNOS and phosphorylated (p)-eNOS at Ser(1177) following SCI in mice. Western blot analysis showed eNOS to be significantly phosphorylated at Ser(1177) from 1 to 2 days after mild SCI, with gradual decrease thereafter. Immunohistochemistry revealed the p-eNOS to be mainly expressed in the endothelial cells of microvessels within gray matter under these conditions. These findings suggest that mild SCI activates eNOS in the subacute stage, which increases spinal cord blood flow and may be involved in protective and repair responses.     

The expression and activity of renal nitric oxide synthase and circulating nitric oxide in polycystic kidney disease rats

Nitric oxide (NO) influences tubular fluid and electrolyte transport, and hence possibly also fluid accumulation in renal cysts. The expression and activity of intrarenal constitutive NO synthase (cNOS) [neuronal NOS, nNOS and endothelial NOS, eNOS] and inducible NOS (iNOS) and plasma nitrite/nitrate (PNOx) concentration were assessed in homozygous Han:SPRD polycystic kidney disease (PKD) rats (cy/cy), heterozygous Han:SPRD PKD rats (cy/+), homozygous normal Han:SPRD littermates (+/+) and Sprague Dawley rats (sd). The results showed: 1) nNOS expression was decreased in proximal tubules and thick ascending limbs of the loop of Henle in cy/cy and cy/+ rats compared to +/+ and sd rats (p<0.05). nNOS was weakly expressed in the epithelium of small cysts and unexpressed in epithelium of large cysts. 2) iNOS expression was increased in proximal tubular epithelial cells in cy/+ rats compared to +/+ rats and sd rats (p<0.01). iNOS expression in cyst epithelium was decreased in cy/+ rats (p<0.05) and absent in cy/cy rats. 3) eNOS expression was similar in the endothelium of intrarenal arteries in all groups. 4) The activity of renal cNOS was decreased in cy/cy and cy/+ rats; the activity of iNOS was decreased only in cy/cy rats, with no significant difference among the other three groups. 5) PNOx concentration was higher in cy/cy rats than in the other three groups, and correlated positively with plasma creatinine and urea. In conclusion, NOS expression and activity decreased as cysts developed, suggesting that NO downregulation is involved in the pathogenesis of PKD.     

Heme oxygenase-2 is present in the sarcolemma region of skeletal muscle fibers and is non-continuously co-localized with nitric oxide synthase-1

There is increasing evidence that the heme oxygenase-2 (HO-2)/carbon monoxide (CO) pathway and the nitric oxide synthase (NOS)/nitric oxide (NO) pathway functionally cross-talk. Therefore, we investigated the appearance of HO-2 in mammalian skeletal muscles where NOS-1 is known to be expressed in high quantities. Immunoblotting of rat hind limb extensor muscles extracts revealed a single 36 kDa band demonstrating the existence of HO-2 in skeletal muscle and indicating the monospecifity of the antibody that was applied. Immunohistochemistry on healthy rat extensor hind limb muscles showed that HO-2 is present in satellite cells, endothelial cells of the vascular system, fibrocytes/fibroblasts but also fiber type-independently in extrafusal myofibers either in association with the non-junctional sarcolemma region, or in a subsarcolemmal network or, less prominently, in cross-striated stripes connected to longitudinally running lines. Combined HO-2 immunohistochemistry and NOS-1 histochemistry revealed an apparent co-localization of both molecules only in the non-junctional sarcolemma region of extrafusal type II myofibers outside costameres. In diseased muscles of mdx mice, HO-2 expression was not changed. In patients suffering from Duchenne's muscular dystrophy, it was absent in the sarcolemma region. In conclusion, the HO-2/CO system is present in mammalian skeletal muscle where it is non-continuously co-localized with the NOS-1/NO-system. This finding implicates an optionally functional cross-talk between both gaseous signaling pathways.     

Expression of nitric oxide synthase and effect of substrate manipulation of the nitric oxide pathway in mouse ovarian follicles

BACKGROUND: Nitric oxide (NO) is a cell messenger with multiple actions in different biological systems, implicated in the control of follicle and oocyte function. NO is formed from L-arginine by isoforms of nitric oxide synthase (NOS) via NG-hydroxy-L-arginine, with L-citrulline as a byproduct. This study aimed to show how modulation of NO by manipulating NOS substrates would affect mouse follicle growth and ovulation in vitro, where vascular effects of NO are attenuated. METHODS: Immunohistochemistry [endothelial (eNOS) and inducible (iNOS)] and in situ hybridization (iNOS) were applied on mouse ovaries. Cultured follicles were also stained for iNOS by immunohistochemistry. For follicles cultured in the presence or absence of L-arginine, the ability of L-citrulline or NG-hydroxy-L-arginine to substitute for L-arginine was assessed in terms of follicle growth and ovulation. RESULTS: iNOS and eNOS were localized in oocytes and theca, with some staining in granulosa. iNOS mRNA occurred predominantly in granulosa and oocyte. Omission of L-arginine significantly reduced follicle survival and ovulation. Partial compensation for L-arginine withdrawal was achieved with L-citrulline and NG-hydroxy-L- arginine. Specific abnormalities of follicle growth were noted. CONCLUSIONS: NOS is present in mouse follicles, and its action is necessary at a local level for normal follicle development in vitro. Reduced growth, persistent basement membranes and reduced ovulation were associated with in vitro disruption of NO.     

巨噬细胞诱导型一氧化氮合酶的表达调节机制

一氧化氮是一种重要的巨噬细胞免疫效应分子,它参与免疫调节和宿主防御反应.一氧化氮的生成主要由诱导型一氧化氮合酶调节,然而诱导型一氧化氮合酶表达的调节机制及信号通路尚不完全清楚.     

Localization of nitric oxide synthase in human trophoblast cells: role of nitric oxide in trophoblast proliferation and differentiation

PROBLEM: There are conflicting reports about the isoform of nitric oxide synthase (NOS) present in trophoblast cells. In this study, we have examined the presence of different NOS isoforms in trophoblast cells. In addition, the role of nitric oxide (NO) in trophoblast function has also been studied by investigating the possible role of nitric oxide in trophoblast proliferation and differentiation. METHOD OF STUDY: NOS isoforms in primary-term trophoblast and JEG-3 cells were identified by immunocytochemistry. The intracellular localization of this enzyme was determined by confocal laser scanning microscopy. Trophoblast proliferation was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasolium bromide (MTT) conversion assay and cellular differentiation was monitored by human chorionic gonodotropin (hCG) and progesterone secretion, measured by radioimmunoassay. RESULTS: The immunoreactive NOS was present in human trophoblast cells of normal term placenta and JEG-3 cells (a choriocarcinoma cell line) maintained in culture. Nicotinamide adenine dinucleotide phosphate (NADPH)-dependent diaphorase activity overlapped with the immunostaining of NOS. Specific antibodies against the different isoforms of NOS detected the presence of neuronal-type NOS (nNOS) only. The other two isoforms, i.e., eNOS (endothelial) and iNOS (macrophage specific) were completely absent. The nNOS was localized in cell cytoplasm. In culture, JEG-3 cells normally undergo proliferation and cytotrophoblast cells in primary culture differentiate to form hormone-secreting syncytial cells. Sodium nitroprusside (SNP), a nitric oxide donor, when added to the culture, significantly increased proliferation of JEG-3 cells and inhibited the differentiation of cytotrophoblast cells. The arrest by SNP in the formation of syncytial cells was further evidenced by the low secretion profile of hCG and progesterone. CONCLUSIONS: Our findings suggest for the first time the presence of nNOS in the human trophoblast cells and a previously unrecognized role of NO in trophoblast proliferation and differentiation.     

人内皮型一氧化氮合酶cDNA在COS-7细胞中的表达

本研究从人脐静脉血管内皮细胞中提取总RNA，采用逆转录PCR(RT-PCR)方法，扩增出人内皮型一氧化氮合酶(heNOS)cDNA，总长度为3731bp。将其克隆入pUCm—T载体质粒，序列分析表明，克隆所得片段含有完整开放阅读框架，与GenBank中heNOScDNA序列同源性达99．93％，在此基础上发现有若干核酸多态性。将该基因片段亚克隆到真核表达载体pcDNA3．0上，用脂质体转染法将pcDNA3．0／heNOS转染到COS-7细胞株，RT—PCR、Western blot分别检测到外源性eNOS基因在mRNA水平和蛋白质水平的表达，分析表明所表达的heNOS蛋白质分子量为145ku；L-^14C-精氨酸掺入同位素法检测证实所表达的eNOS蛋白具有生物学活性，能将精氨酸氧化为瓜氨酸。     

Relation between exhaled carbon monoxide levels and clinical severity of asthma

Carbon monoxide (CO) can be detected in exhaled air and is increased in asthmatic patients not treated with corticosteroids. However, it is uncertain whether exhaled CO is related to severity of asthma. To study whether exhaled CO is related to severity of asthma in clinical courses, exhaled CO concentrations were measured on a CO monitor by vital capacity manoeuvre in 20 mild asthmatics treated with inhaled beta2-agonists alone, 20 moderate asthmatics treated with inhaled corticosteroids, and 15 stable asthmatics treated with high dose inhaled corticosteroids and oral corticosteroids once a month over 1 years. Exhaled CO concentrations were also measured in 16 unstable severe asthmatics who visited the hospital every 7 or 14 days for treatment with high dose inhaled corticosteroids and oral corticosteroids. The mean values of exhaled CO in severe asthma over 1 year were 6.7 +/- 9.5 p.p.m. (n = 31, mean +/- SD) and significantly higher than those of non-smoking control subjects (1.2 +/- 0.9 p.p.m., n = 20, P < 0.01). Exhaled CO concentrations in unstable severe asthmatics were significantly higher than those in stable severe asthmatics. However, exhaled CO concentrations in mild and moderate asthmatics did not differ significantly from those in non-smoking control subjects (P > 0.20). There was a significant relationship between the exhaled CO concentrations and forced expiratory volume in one second in all asthmatic patients. These findings suggest that exhaled CO concentrations may relate to the severity of asthma and measurements of exhaled CO concentrations may be a useful means of monitoring airway inflammation in asthma.     

兔动脉粥样硬化形成过程中血清NOS活性的变化

目的研究兔动脉粥样硬化形成过程中血一氧化氮合酶(NOS)活性的变化及其作用。方法将30只长耳白兔随机分为3组:普通饮食组、高脂饮食组、球囊损伤 高脂饮食组,每组10只,3个月后以中国斑点蝰蛇毒和组胺触发使斑块破裂。生化监测血脂、血清NO、NOS及OH-水平,病理检查动脉硬化斑块。结果高脂饮食组、球囊损伤 高脂饮食组血脂水平明显增高;血清NO水平在药物触发及斑块破裂后明显减少;NOS活性及OH-水平在高脂喂养后明显升高,药物触发后明显减少。结论动脉粥样硬化早期NOS活性增强,内皮功能得到代偿;斑块处于不稳定状态时,NOS活性明显下降,内皮功能明显受损进入失代偿状态。