骨髓间充质干细胞移植修复动脉粥样硬化破裂斑块的研究

目的研究骨髓间充质干细胞(MSC)移植对动脉粥样硬化破裂斑块的修复作用。方法选择24只雄性新西兰白兔,采用自创液氮冻伤术,随机各取2只兔制备动脉粥样硬化斑块形成及斑块破裂模型,将剩余兔再随机分为移植组10只,对照组10只。ELISA法检测治疗前后血清基质金属蛋白酶9(MMP-9)、高敏C反应蛋白(hs-CRP)及纤溶酶原激活物抑制剂1(PAI-1)的变化。HE染色和Masson三色染色,光镜观察斑块修复情况;免疫组织化学法检测5-溴脱氧尿核苷标记的阳性细胞。结果 MSC移植4周后,移植组新生内皮细胞及胶原纤维明显增多;移植组斑块区5-溴脱氧尿核苷标记的阳性细胞明显增多;MSC移植4周后,与对照组比较,移植组MMP-9、hs-CRP及PAI-1水平明显降低(P<0.01)。结论 MSC移植可增加内皮细胞及胶原纤维数量,降低炎性因子及凝血纤溶因子,从而起到稳定与修复破裂斑块作用。     

Low-density lipoproteins induce the polar secretion of PAI-1 by endothelial cells in culture

Patients with hypercholesterolemia and with coronary atherosclerosis have increased plasma levels of plasminogen activator inhibitor (PAI)-1. PAI-1 and low-density lipoproteins (LDL) are also present in the walls of atherosclerotic vessels, where they participate in the development and remodeling of the atherosclerotic plaques. We investigated the influence of LDL on the apical (luminal) and basolateral (subendothelial) secretion of PAI-1 by human umbilical vein endothelial cells in a two-compartment cell-culture model. Confluent cells were incubated with LDL either in the apical compartment or in the basal compartment. Cells incubated with culture medium served as controls. A significantly higher concentration of PAI-1 was found in both the apical (P = 0.025) and the basal compartment (P = 0.025) if cells were incubated with LDL on the basolateral side. In contrast, incubation of the cells with LDL apically resulted in an increased PAI-1 concentration only in the apical compartment (P = 0.028) and not in the basal compartment. Our findings indicate that the LDL particles that reach the subendothelial space can induce an increased release of PAI-1 by endothelial cells into the vessel lumen and also contribute to the release of PAI-1 into the subendothelial space and thus to the process of atherosclerotic plaque remodeling.     

Overexpression of heme oxygenase-1 in coronary atherosclerosis of Japanese autopsies with diabetes mellitus: Hisayama study

Few studies regarding the topographical expression of heme oxygenase-1 (HO-1) and its pathophysiological role in human coronary atherosclerotic lesions, particularly in relation to type 2 diabetes mellitus (DM) and intimal angiogenesis, have been reported. HO-1 expression was immunohistochemically examined in 312 tissue blocks of coronary arteries obtained from 53 Japanese autopsy cases in Hisayama cohort study that included 19 diabetic subjects and 34 age- and sex-matched non-diabetic subjects (56-93 years old, mean+/-S.D.: 73+/-10). The HO-1 was ubiquitously distributed in atherosclerotic intima, and was mainly expressed by macrophages and endothelial cells, and partly by smooth muscle cells. The prevalence of HO-1 expression increased as the lesion type (as classified by the American Heart Association (AHA) Committee) and stenotic grade progressed (p<0.0001), and was significantly higher in diabetic than in non-diabetic subjects (p<0.01). This HO-1 overexpression was associated with greater CD-68-positive macrophage infiltration (p=0.005). Interestingly, the distribution of HO-1-positive cells was accentuated in coronary atherosclerotic lesions with intimal microvessels in diabetic subjects (p<0.05), particularly those with hypercholesterolemia (p<0.05), and was preferentially distributed in the shoulder region of atherosclerotic lesion type IV in the AHA classification (p<0.01). In conclusion, HO-1 expression was distributed in overall human coronary atherosclerotic lesions, particularly in diabetic subjects, indicating that HO-1 expression is intimately associated with atherogenesis and may play an important role as an adaptive molecule in the inflammatory-repair process. The association of HO-1 overexpression with a greater extent of intraplaque angiogenesis suggests a multi-faceted role for HO-1 in modulating the progression of atherosclerosis.     

Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries.

Decreased fibrinolytic capacity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. To investigate the potential role of this inhibitor in atherosclerosis, we examined the expression of PAI-1 mRNA in segments of 11 severely diseased and 5 relatively normal human arteries obtained from 16 different patients undergoing reconstructive surgery for aortic occlusive or aneurysmal disease. Densitometric scanning of RNA (Northern) blot autoradiograms revealed significantly increased levels of PAI-1 mRNA in severely atherosclerotic vessels (mean densitometric value, 1.7 +/- 0.28 SEM) compared with normal or mildly affected arteries (mean densitometric value, 0.63 +/- 0.09 SEM; P less than 0.05). In most instances, the level of PAI-1 mRNA was correlated with the degree of atherosclerosis. Analysis of adjacent tissue sections from the same patients by in situ hybridization demonstrated an abundance of PAI-1 mRNA-positive cells within the thickened intima of atherosclerotic arteries, mainly around the base of the plaque. PAI-1 mRNA could also be detected in cells scattered within the necrotic material and in endothelial cells of adventitial vessels. In contrast to these results, PAI-1 mRNA was visualized primarily within luminal endothelial cells of normal-appearing aortic tissue. Our data provide initial evidence for the increased expression of PAI-1 mRNA in severely atherosclerotic human arteries and suggest a role for PAI-1 in the progression of human atherosclerotic disease.     

Local plasminogen activator inhibitor type 1 overexpression in rat carotid artery enhances thrombosis and endothelial regeneration while inhibiting intimal thickening

Elevated levels of plasminogen activator inhibitor type 1 (PAI-1) are found in advanced atherosclerotic plaque compared with normal vessel and may contribute to plaque progression and complications associated with plaque rupture. Increased expression of PAI-1 probably contributes to the thrombotic properties of advanced atherosclerotic plaque by impeding plasmin generation and degradation of fibrin. To test this hypothesis, we have deliberately created synthetic neointimas by seeding onto the denuded luminal surface of rat carotid arteries smooth muscle cells transduced with replication-defective retrovirus encoding rat PAI-1. This cell-based gene transfer method results in stable, long-term, and localized gene expression. PAI-1 overexpression increases mural thrombus accumulation at 4 days but decreases neointimal area by 30% and 25% at 1 week and 2 weeks, respectively. PAI-1 overexpression accelerates reendothelialization of injured arteries compared with control arteries at 1 week, 2 weeks, and 1 month. PAI-1 overexpression does not alter matrix accumulation at 1 week. Increased PAI-1 expression in the rat carotid artery enhances thrombosis and endothelial regeneration while inhibiting intimal thickening. These results suggest that PAI-1 could play a direct role in the development of advanced atherosclerotic plaque and in the repair of the diseased vessel after fibrous cap disruption.     

Collagen-synthesizing cells in initial and advanced atherosclerotic lesions of human aorta

Accumulation of extracellular matrix, fibrosis, is regarded to be one of the major manifestations of atherosclerosis. Collagen type I is the predominant matrix component in human atherosclerotic plaques. In this work we have demonstrated procollagen type I expressing cells (PCl-cells) and studied their localization in grossly normal human aorta and atherosclerotic lesions: initial lesions, fatty streaks, fibrolipid lesions (fibrolipid plaque, fibroatheroma), fibrotic lesions (fibrous plaque). PCl-cells were revealed immunocytochemically using SPI.D8 monoclonal antibody against human procollagen type I. We failed to detect PCl-cells in the areas of grossly normal aorta and media underlying atherosclerotic lesions. Positively stained cells were shown in the areas of initial lesions, fatty streaks, fibrolipid and fibrous plaques. The largest amount of PCl-cells was revealed in fatty streaks. These cells were predominantly localized in the preluminal proteoglycan-rich intimal sublayer. Intimal cells in grossly normal regions formed a common cellular network contacting each other with their processes. The cellular network is found to be partly disintegrated in atherosclerotic lesions, which leads to the appearance of isolated cells. The share of isolated PCl-cells localized outside the intimal cellular network was higher in advanced lesions than in the areas of early atherosclerotic lesions. In initial lesions most of PCl-cells were identified as smooth muscle cells using antibodies to smooth muscle -actin. In fatty streaks PCl-expressing smooth muscle cells were fewer in number. Much fewer cells double-stained with anti--actin and anti-PCI antibodies were found in fibrolipid and fibrous plaques. The proportion of these double stained cells was higher among total number of PCl-cells involved in the cellular network versus PCl-cells outside the network. The results of the study demonstrated that the most active de novo synthesis of interstitial collagen takes place in the regions of atherosclerotic lesions characterized by lipid deposition, which may lead to the further progression of atherosclerotic lesions.     

Immunoelectron-microscopic localization of S-protein/vitronectin in human atherosclerotic wall

S-protein/vitronectin is a multifunctional glycoprotein interacting with both complement activation and coagulation pathways. Its presence was investigated in 5 femoral and 5 iliac atherosclerotic human arteries, obtained at surgery, by immunoelectron microscopy using an affinity purified rabbit IgG specific for human S-protein/vitronectin. The immunoelectron dense specific deposits were found in both intimal thickenings and fibrous plaques in association with elastic fibers, collagen bundles and cell debris in the vicinity of elastin. Cell debris embedded in the collagen matrix were S-protein/vitronectin negative. S-protein/vitronectin was also absent on intact cells, lipid droplets and cholesterol clefts. All cell debris, however, was positive for C5b-9 deposits suggesting that complement activation had occurred at these sites with or without S-protein/vitronectin interaction. S-protein/vitronectin may play a role in the arterial wall defence by restricting the extent of complement activation.     

Intimal smooth muscle cells of porcine and human coronary artery express S100A4, a marker of the rhomboid phenotype in vitro

We reported that smooth muscle cell (SMC) populations isolated from normal porcine coronary artery media exhibit distinct phenotypes: spindle-shaped (S) and rhomboid (R). R-SMCs are recovered in higher proportion from stent-induced intimal thickening compared with media suggesting that they participate in intimal thickening formation. Our aim was to identify a marker of R-SMCs in vitro and to explore its possible expression in vivo. S- and R-SMC protein extracts were compared by means of 2-dimensional polyacrylamide gel electrophoresis followed by tandem mass spectrometry. S100A4 was found to be predominantly expressed in R-SMC extracts. Using a monoclonal S100A4 antibody we confirmed that S100A4 is highly expressed by R-SMCs and hardly detectable in S-SMCs. S100A4 was colocalized with alpha-smooth muscle actin in stress fibers of several quiescent cells and upregulated during migration. PDGF-BB, FGF-2 or coculture with endothelial cells, which modulate S-SMCs to a R-phenotype, increased S100A4 expression in both S- and R-SMCs. Silencing of S100A4 mRNA in R-SMCs decreased cell proliferation, suggesting a functional role for this protein. In vivo S100A4 was absent in normal porcine coronary artery media, but highly expressed by SMCs of stent-induced intimal thickening. In humans, S100A4 was barely detectable in coronary artery media and markedly expressed in SMCs of atheromatous and restenotic coronary artery lesions. Our results indicate that S100A4 is a marker of porcine R-SMCs in vitro and of intimal SMCs during intimal thickening development. It is also a marker of a large population of human atheromatous and restenotic SMCs. Clarifying S100A4 function might be useful to understand the evolution of atherosclerotic and restenotic processes.     

Menschliche kardiale mikro- und makrovaskul?re Endothelzellen zeigen ein unterschiedliches Expressionsmuster von Adh?sionsmolekülen und reagieren unterschiedlich auf oxidierte LDL

While the cellular mechanisms of atherosclerosis have been intensively studied, the mechanisms leading to preferential localization of atherosclerotic lesions are less well understood. To further define these mechanisms, endothelial cells from coronary arteries, i.e., vessels with frequent atherosclerotic lesions, were isolated and grown in vitro. In order to compare the reactions of both cell types, endothelial cells derived from microvessels of human hearts were isolated and cultured under identical conditions. Incubation of endothelial cells with oxidized LDL (75 microg/ml protein) induced a significant increase in PAI-1 activity (182%, p < 0.05) in coronary macrovascular endothelial cells. This stimulatory effect of ox-LDL was less significant in microvascular endothelial cells (144%, p < 0.05). n-LDL did not influence secreted PAI-1 activity. Stimulation with angiotensin II induced expression of E-selectin more effectively in coronary macrovascular than in microvascular endothelial cells. In addition, angiotensin II-induced E-selectin expression led to increased E-selectin-dependent adhesion of HL60 cells to coronary macrovascular endothelial cells under flow conditions, while only little effect was observed with cardiac microvascular endothelial cells. In contrast, L-selectin-dependent adhesion, which has been shown to play an important role in inflammatory reactions, was preferentially observed in cardiac microvascular endothelial cells and could only be stimulated with TNFalpha, not by angiotensin II. Therefore, these cellular differences may in part explain specific properties of cardiac endothelial cells: Such that atherosclerotic lesions are localized in macrovascular vessel segments, whereas inflammatory responses are predominantly found in the microvasculature.     

Mechanisms of TGF-beta1-induced intimal growth: plasminogen-independent activities of plasminogen activator inhibitor-1 and heterogeneous origin of intimal cells

Transforming growth factor (TGF)-beta(1) is a potent stimulator of intimal growth. We showed previously that TGF-beta(1) stimulates intimal growth through early upregulation of plasminogen activator inhibitor-1 (PAI-1) and, subsequently, PAI-1-dependent increases in cell migration and matrix accumulation. We also showed that PAI-1 negatively regulates TGF-beta(1) expression in the artery wall. Here we use plasminogen-deficient mice to test whether TGF-beta(1)-stimulated, PAI-1-dependent intimal growth and PAI-1 suppression of TGF-beta(1) expression are mediated through inhibition of plasminogen activation by PAI-1. We also use lineage tracing to investigate the origin of cells in TGF-beta(1)-induced intimas. Surprisingly, both TGF-beta(1)-induced, PAI-1-dependent intimal growth and PAI-1 suppression of TGF-beta(1) expression are independent of plasminogen. Moreover, approximately 50% of cells that migrate into the intima of TGF-beta(1)-overexpressing arteries carry a smooth muscle lineage marker, <1% carry a bone marrow lineage marker, and the remaining cells carry neither marker. Therefore, PAI-1 stimulates intimal growth and suppresses TGF-beta(1) expression through activities other than inhibition of plasminogen activation. In addition, contrary to widely held models, our results do not support a role for plasmin (or thrombospondin) in TGF-beta(1) activation in the artery wall. Further identification of the molecular targets through which PAI-1 stimulates intimal formation and suppresses TGF-beta(1) expression in the artery wall may reveal new approaches for inhibiting intimal formation. Our studies also discount bone marrow as an important source from which TGF-beta(1) recruits intimal cells and suggest instead that TGF-beta(1) induces substantial cell migration either from the adventitia or from an extravascular, but nonhematopoietic source.     

Stent design related neointimal tissue proliferation in human coronary arteries; an intravascular ultrasound study.

AIMS: Histological restenosis models in animals have indicated that stent design has a significant impact on vessel trauma during stent implantation and on the amount of subsequent neointimal tissue proliferation. The impact of different stent designs on intimal hyperplasia in human atherosclerotic coronary arteries has not been determined. METHODS AND RESULTS: Angiographic and intravascular ultrasound studies were performed at the 6 month follow-up in 131 consecutive native coronary lesions of 131 patients treated with 50 Multi-Link stents, 40 InFlow stents and 41 Palmaz-Schatz stents. Lumen and stent cross-sectional areas (CSA) were measured at 1 mm axial increments. Mean intimal hyperplasia cross-sectional area (stent CSA-lumen CSA) and mean intimal hyperplasia thickness were calculated. Intravascular ultrasound demonstrated different levels of intimal hyperplasia proliferation for the three stents. Mean intimal hyperplasia thickness was 0.16+/-0.08 mm for Multi-Link stents, 0.26+/-0.19 mm for Palmaz-Schatz stents and 0.39+/-0.14 mm for Inflow stents (P<0.001). Multivariate analysis proved that stent type was the only independent predictor of intimal hyperplasia thickness at follow-up (P<0.001). CONCLUSION: Coronary stent design has a significant impact on subsequent intimal hyperplasia after implantation into atherosclerotic human coronary arteries. The corrugated ring design of the Multi-Link stent proved to result in less tissue proliferation at 6-month follow-up than the tubular slotted design of Palmaz-Schatz and InFlow stents.     

Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice

Epidemiological studies suggest that elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) predispose an individual to ischemic heart disease or promote plaque progression by inhibiting fibrinolysis. In the present study, loss of PAI-1 in apolipoprotein E (apoE)-deficient (apoE(-/-):PAI-1(-/-)) mice promoted the growth of advanced atherosclerotic plaques, which was due to enhanced extracellular matrix deposition. ApoE(-/-):PAI-1(-/-) plaques also exhibited collagen fiber disorganization and degradation. Immunostaining and bone marrow transplantation revealed that smooth muscle cells, not macrophages, primarily expressed PAI-1 in plaques. Thus, although PAI-1 may promote plaque growth because of its antifibrinolytic properties, the present study reveals a protective role for PAI-1 by limiting plaque growth and preventing abnormal matrix remodeling.     

C-type natriuretic peptide (CNP) suppresses plasminogen activator inhibitor-1 (PAI-1) in vivo

OBJECTIVE: Elevated vascular plasminogen activator inhibitor-1 (PAI-1) levels are associated with atherosclerosis. In vitro, C-type natriuretic peptide (CNP) has anti-proliferative effects and inhibits the production of PAI-1 in cultured vascular cells. Whether CNP can affect PAI-1 in vivo, particularly in the setting of atherosclerosis, has not been reported. METHODS: Using the rabbit carotid arterial collar model of intimal hyperplasia (collar in place for 7 days), PAI-1 protein was compared in normal, vehicle (saline)-collared, and CNP-treated-collared arteries from the same animal. PAI-1 levels were measured by immunohistochemistry and densitometry and by Western blot. CNP was either infused into the peri-arterial space within one collar (10 fmol/h) or infused directly into the arterial lumen under one collar (100 pmol/h). In some rabbits (n=8), superoxide production in collared and normal artery segments was measured in vitro by chemiluminescence. RESULTS: PAI-1 was present throughout the vascular wall. Endothelial PAI-1 was elevated in saline-collared arteries (approximately 16%, P<0.05; n=7 rabbits) compared with normal carotid segments. The collar induced both a neointima that contained PAI-1 and the accumulation of macrophages in the adventitia. Peri-arterial CNP reduced PAI-1 (P<0.05) in the endothelium (33%), adventitia (47%) and neointima (39%), compared with levels in the contralateral, saline-collared carotid artery, while macrophage infiltration was reduced. Elevated superoxide production in collared arteries was not altered by chronic in vivo treatment with CNP (n=8). Peri-arterial CNP treatment did not reduce intimal thickening. Intra-luminal CNP (n=6) reduced endothelial, neointimal and total vessel (Western blot) PAI-1, macrophage accumulation, and intimal thickening (all P<0.05). CONCLUSIONS: CNP treatment of collared carotid arteries in vivo for 1 week suppressed endothelial and neointimal PAI-1, independently of intimal thickening. The CNP effects were not via superoxide. This is the first evidence that CNP inhibits activated PAI-1, in vivo.     

Characterization of the atherosclerotic plaque in the internal mammary artery

The current study examines, at both structural and ultrastructural levels, representative segments of internal mammary arteries obtained from 15 male patients, ranging in age from 45 to 75 years, with signs or symptoms of coronary heart disease. These segments were obtained at the time of coronary bypass surgery. Of the 15 segments examined, only 2 were found to have atherosclerotic plaques. In other segments, only an intimal thickening similar to that observed during aging was found. There was evidence of endothelial cell loss and defects of internal elastic lamina in the present study; however, there was no evidence of lipid accumulation in the intimal region. This observation agrees with previous findings that indicate that lipid accumulation is not a necessary factor for the formation of atherosclerotic plaques. During the study microfilament bundles, the so-called “stress fibers,” were also observed in the cytoplasm of the luminal side of endothelial cells. Stress fibers are known to be present in some endothelial cells in some pathologies such as regeneration after injury or hypertension. One of the features of the atherosclerotic plaques from an internal mammary artery was the presence of cells with contractile and synthetic phenotypes (contractile and synthetic smooth muscle cells), as well as cells with intermediate features. Cells with similar characteristics have also been observed during the development of the early stages of atherosclerosis, during embryological development of vessels, after experimental excimer laser treatment, and in primary cell culture. To our knowledge, this is the first report showing the ultrastructural features of the atherosclerotic plaques in the internal mammary artery. Cathet. Cardiovasc. Diagn. 43:413–420, 1998. © 1998 Wiley-Liss, Inc.     

Expression of parathyroid hormone-related protein in human and experimental atherosclerotic lesions: functional role in arterial intimal thickening

We investigated the expression of parathyroid hormone-related protein (PTHrP) in atherosclerotic lesions and the role of PTHrP in the development of arterial neointima formation. Immunohistochemical staining of PTHrP in the neointima of rat aorta produced by balloon injury and of rat femoral artery produced by non-obstructive polyethylene cuff placement, and in the atherosclerotic lesion of human coronary artery was performed using anti-human PTHrP-(1-34) antibody. Anti-muscle actin antibody, HHF-35, and anti-macrophage antibody, HAM-56, were used to identify smooth muscle cells and macrophages, respectively. Immunoreactivity of PTHrP was detected in the thickened intima of rat and human lesions where the predominant cell types were smooth muscle cells or macrophages dependently on the lesion type. In the next series of experiments, we examined the effect of PTHrP on the development of cuff-induced intimal thickening of rat femoral artery. Either PTHrP-(1-34) or PTHrP-(7-34), a PTH/PTHrP receptor antagonist, suspended in pluronic F-127 gel was locally applied around the rat femoral artery. Intimal thickening induced by cuff placement was evaluated 2 weeks later. PTHrP-(1-34) dose-dependently inhibited intimal thickening determined as intima/media ratio and % stenosis whereas PTHrP-(7-34) dose-dependently enhanced that. These results suggest that PTHrP, which is expressed in atherosclerotic lesions, inhibits the development of neointimal formation.     

Ciglitazone抑制人肝星状细胞外基质蛋白表达的分子机制

目的探讨过氧化物酶体增殖物激活受体（PPARγ）配体是否通过阻断肝星状细胞的TGF β1型受体（TGF βR1）信号途径，阻止Smad3磷酸化而抑制纤溶酶原激活物抑制剂1（PAI-1）、胶原蛋白1αI的表达，发挥其抗纤维化的作用。方法用促进脂肪细胞分化的培养液预处理人肝星状细胞LX-2，使其呈现脂肪细胞的某些表型，从活化状态转为静止型，分别加用TGF β1或TGF β1加TGF βR1激酶抑制剂SB431542或TGF β1加PPAR γ配体Ciglitazone处理LX-2细胞。分别用荧光实时定量PCR、Western blot、荧光素酶分析的方法检测PPAR γ配体对LX-2细胞用TGF β1诱导前后Smad3磷酸化水平、PAI-1的mRNA与蛋白表达水平和PAI-1启动子活性、胶原蛋白1αI mRNA表达水平的影响。结果诱导脂肪细胞分化的培养液可使LX-2细胞出现脂质沉积与静止型肝星状细胞的标志物之一PPAR γ表达的增加。TGFD1以剂量和时间依赖的方式增加细胞外基质蛋白的表达，胶原蛋白1aI和PAI-1 mRNA的表达在3h内增加3倍，PAI-1蛋白的表达在6h内增加8倍。TGF β1诱导的Smad3磷酸化导致胶原蛋白1aI和PAI-1表达增加。PPARγ配体Ciglitazone与TGF βR1激酶抑制剂SB431542，均以剂量依赖的方式阻断TGF β1的上述作用，10μmol／L SB431542、10μmol／L的Ciglitazone可以阻断TGF β1诱导的Smad3磷酸化、胶原蛋白1αI mRNA、PAI-1 mRNA和蛋白的表达。结论PPAR γ配体Ciglitazone抗纤维化作用可能与其对TGF β1-TGF βR1信号传导、Smad3磷酸化的阻断作用有关，进而抑制胶原蛋白1αI和PAI-1的表达。     

Characterization of the fluorescent morphological structures in human arterial wall using ultraviolet-excited microspectrofluorimetry

In this study, the fluorescent morphological structures in normal coronary artery, normal aorta, and atherosclerotic aorta were histochemically identified and spectroscopically characterized in situ using ultraviolet-excited microspectrofluorimetry. Excitation wavelengths of 290 nm and 310/312 nm were employed to observe two distinct fluorescence bands, with peak emission wavelengths near 335 nm and 380 nm, respectively. Emission of the short wavelength 335 nm band, previously assigned to tryptophan residues in tryptophan-containing proteins, was observed from all the morphological structures in the vessel walls and was isolated in groups of smooth muscle cells in aorta and coronary artery media. The long wavelength 380 nm band was assigned to distinct fluorophores associated with the structural proteins collagen and elastin and was observed in collagen fibers and elastic fibers, respectively. The corresponding morphological structures in normal aorta, normal coronary artery, and atherosclerotic aorta exhibited similar fluorescence lineshapes. In atherosclerotic plaque, a distinct fluorescence band, peaking near 370 nm, was observed in the emission from both ceroid granules and necrotic core. Using a simple, quantitative model, differing contributions of collagen, elastin, and tryptophan-containing protein fluorescence were shown to account for over 95% of the emission from the intima, media, and adventitia layers of non-necrotic aorta and coronary artery.     

Plaque rupture possibly induced by coronary spasm--an autopsy case of acute myocardial infarction

The histological picture of sites of coronary spasms has not yet been made sufficiently clear. A histopathological examination was performed on the coronary artery of a patient who died of acute myocardial infarction after a refractory coronary spasm was identified by coronary arteriography. In the site of the coronary spasm, intimal bleeding as well as infiltration by lymphocytes and plasma cells in the adventitia were seen. In the same region, fracture of intimal collagen fibers and rupture of atheromatous plaque were observed. Although it is very difficult to prove in individual cases of acute myocardial infarction that spasms played a part, some cases involving spasms may possibly exist among the cases of acute myocardial infarction showing atheromatous plaque rupture--thrombus formation.     

Restenosis after percutaneous transluminal coronary angioplasty: pathologic observations in 20 patients

Histopathologic examination was performed in 20 patients undergoing antemortem coronary angioplasty. Thirty-four lesions were dilated and the interval between coronary angioplasty and death ranged from several hours to 4 years. Intimal proliferation of smooth muscle cells, as a major cause of restenosis, was observed in 83% to 100% of 28 lesions examined 11 days to 2 years after coronary angioplasty. In 20 lesions examined within 6 months, proliferating smooth muscle cells were predominantly of the synthetic type and there was abundant extracellular matrix substance chiefly composed of proteoglycans. In eight lesions examined between 6 months and 2 years, contractile type smooth muscle cells were dominant and extracellular matrix was composed chiefly of collagen. In three lesions examined after 2 years, evidence of antemortem coronary angioplasty was hardly identifiable and these lesions were almost indistinguishable from conventional atherosclerotic plaque. These temporal changes in histologic pattern provide a pathologic background for clinical reports that restenosis is predominantly found within 6 months after coronary angioplasty. Morphometric analysis revealed that the extent of intimal proliferation was significantly greater in lesions with evidence of medial or adventitial tears than in lesions with no or only intimal tears.