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Endoglin is a transmembrane protein that is found in association with transforming growth factor-beta (TGF-beta) superfamily receptor complexes and has an expression pattern that appears to be restricted primarily to endothelial cells, activated macrophages, trophoblasts, and fibroblasts. Since mutations in endoglin have been shown to be linked to hereditary hemorrhagic telangiectasia type 1, a disease manifested as vascular malformations characterized by excessive layers of vascular smooth muscle cells (VSMC), the expression of endoglin was investigated in VSMC. In vivo, the majority of SMC in human atherosclerotic plaques expressed high levels of endoglin, while endoglin was not detected in SMC from samples of the normal arterial wall. In vitro studies demonstrate that human aortic smooth muscle cells (HASMC) express the L-isoform of endoglin. Like endothelial cells, HASMC express endoglin protein as a dimer on the cell surface that binds TGF-beta1. In vitro, endoglin expression by HASMC is upregulated in response to TGF-beta1, suggesting that the presence of this factor in the atherosclerotic plaque might be responsible for the increased expression of endoglin. The demonstration of increased levels of endoglin in VSMC in human atherosclerotic plaques suggests a role for SMC endoglin in the maintenance of vascular integrity and in the response of the vessel wall to injury.  相似文献   

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Background

Mitochondrial DNA damage has been implicated in atherosclerosis but whether it is sufficient to induce mitochondrial dysfunction is unclear. Here we investigated the bioenergetics of human atherosclerotic plaques and the effects of atherogenic lipids on mitochondrial respiration and turnover in vascular smooth muscle cells (VSMCs).

Methods

Human atherosclerotic plaques derived from patients undergoing carotid endarterectomy were dissected into defined regions including healthy media, shoulder region, fibrous cap, and core. Their bioenergetic profiles were investigated with an extracellular flux analyser (Seahorse, Agilent Technologies, Santa Clara, CA, USA). VSMCs derived from rat or human aortas were treated with oxidised LDL (OxLDL) before extracellular flux analysis and assessment of mitophagy using the mitochondrially targeted keima reporter.

Findings

The basal oxygen consumption rate was similar across human atherosclerotic regions (five plaques, 25 samples per region). However, respiration after uncoupling with p-(tri-fluromethoxy)phenyl-hydrazone (FCCP) was significantly induced in the healthy media (mean 210% of baseline [SD 53], p=0·0017) and shoulder region (169% [47], p=0·0048) but not in the diseased fibrous cap (128% [43], p=0·15) or core (127% [32], p=0·10) regions. OxLDL decreased basal respiration in a dose-dependent manner (OxLDL at 100 μg/mL concentration mean 7·0 pmol/min per μg protein [SD 2·17] vs control 10·10 [2·86], p<0·0001), and FCCP induced respiration of rat VSMCs (8·60 [3·37] vs 14·10 [5·21], p<0·0001) and induced mitophagy in human VSMCs (0·43 arbitrary units [0·20] vs 0·15 [0·18], p=0·0007).

Interpretation

We show that mitochondrial damage in human atherosclerotic plaques is sufficient to affect their function. Atherogenic lipids cause changes in mitochondrial metabolism and induce mitophagy in human VSMCs. Knowledge of the role of mitochondrial bioenergetics and turnover is important for our understanding of disease progression and could lead to future therapeutic targets.

Funding

Wellcome Trust, British Heart Foundation, Medical Research Council.  相似文献   

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牛磺酸是一种条件必须氨基酸,是细胞内高丰度的一种自由氨基酸。牛磺酸主要通过牛磺酸转运体(Taurine transporter,TAUT)摄入细胞。本研究探讨牛磺酸转运体在血管平滑肌细胞内的表达。通过RT-PCR,测定TAUT基因在血管平滑肌细胞mRNA的表达,利用Western blot和免疫组织化学方法检测TAUT在血管平滑肌细胞蛋白的表达。体外培养的大鼠血管平滑肌细胞和大鼠主动脉组织切片中血管平滑肌细胞均可表达TAUT。血管平滑肌细胞可转录及翻译TAUT。  相似文献   

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Cartilage oligomeric matrix protein (COMP/thrombospondin [TSP]-5) belongs to the thrombospondin gene family and is an extracellular glycoprotein found predominantly in cartilage and tendon. To date, there is limited evidence of COMP/TSP-5 expression outside of the skeletal system. The aim of the present study was to investigate the expression of COMP/TSP-5 in cultured human vascular smooth muscle cells and human arteries. COMP/TSP-5 mRNA and protein expression was detected in cultured human vascular smooth muscle cells with both Northern blotting and immunoprecipitation. Serum, as well as transforming growth factor (TGF)beta1 and TGF-beta3, stimulated COMP/TSP-5 mRNA expression. COMP/TSP-5 was detected in normal as well as atherosclerotic and restenotic human arteries with immunohistochemistry. The majority of COMP/TSP-5 was expressed in close proximity to vascular smooth muscle cells. In vitro attachment assays demonstrated strong adhesion of smooth muscle cells to COMP/TSP-5-coated surfaces, with the majority of cells spreading and forming stress fibers. In addition, COMP/TSP-5 supported the migration of smooth muscle cells in vitro. The present study shows that COMP/TSP-5 is present in human arteries and may play a role in the adhesion and migration of vascular smooth muscle cells during vasculogenesis and in vascular disease settings such as atherosclerosis.  相似文献   

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CD40-CD154-mediated signaling has recently been described as playing a role in cellular functions involved in atherosclerotic processes. CD40 is expressed in macrophages, lymphocytes, endothelial cells, and vascular smooth muscle cells. However, cross-sectional studies investigating the expression of CD40 in atherosclerotic lesions are lacking. In the present study the expression of CD40 was studied in atherosclerotic lesions from 43 patients classified according to the World Health Organization criteria. Serial immunohistologic stainings of human iliac arteries from 43 patients were performed using monoclonal antibodies. Lesions were classified according to World Health Organization criteria, and CD40 expression was analyzed with regard to cell morphology and cellular markers by 2 independent observers. Human atherosclerotic lesions revealed a significant increase in intimal thickness, number of inflammatory infiltrates, and CD40-positive macrophages and vascular smooth muscle cells with progression of the lesions. This increase was most prominent from stage 0 to stage I. A significant correlation between intimal thickness and CD40-positive macrophages (r = 0.75, p <0.0005) and CD40-positive vascular smooth muscle cells (r = 0.81, p <0.0005) was observed. Ligation of the cellular CD40 receptor contributes to inflammatory cellular events in human vascular smooth muscle cells. These data suggest a direct association of CD40 expression in atherosclerotic lesions with early plaque development.  相似文献   

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Cultured human arterial smooth muscle cells produced an immunologically specific renin-like enzyme. The renin-like enzyme in the culture medium was mostly an inactive form; the proportion of the active form in the cell was 30 to 75%. Phorbol 12-myristate 13-acetate, N'-O'-dibutylyladenosine 3', 5'-monophosphate and isoproterenol with theophylline increased the renin-like enzyme in the medium and in the cell, dose dependently. Endothelial cell growth supplement also increased the renin-like enzyme produced by cultured vascular smooth muscle cells, and heparin promoted the effects of endothelial cell growth supplement. The existence of the regulation of the renin-like enzyme produced by cultured vascular smooth muscle cells strongly suggests the existence of a local renin angiotensin system in human vascular walls.  相似文献   

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While the hypocholesterolemic effects of taurine have extensively been studied using experimental animals, the anti-atherosclerotic effects of taurine have been given less attention. We examined the effect of taurine on atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits. Treatment of WHHL rabbits with taurine (0.3% in drinking tap water) for 24 weeks decreased aortic lesions by 31%, estimated as intimal thickening. Taurine significantly decreased cholesteryl ester content of aortic arch, thoracic aorta, and abdominal aorta by 35, 43, and 54%, respectively. Concomitantly, activity of acyl-CoA:cholesterol acyltransferase (ACAT), an enzyme responsible for cholesterol esterification, was also significantly decreased. Immunohistochemical analysis revealed decreased macrophages in the intima of taurine-treated rabbits. Taurine had no apparent effect on blood pressure and serum cholesterol levels. Contents of thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, was reduced in serum and aorta by 29 and 50%, respectively, when taurine was ingested. In addition, LDL from taurine-treated rabbits was resistant to copper-induced oxidative modification. These results revealed that taurine prevents development of atherosclerosis and that the anti-atherosclerotic effects of taurine are independent of serum cholesterol levels. The anti-oxidant action of taurine may be involved in inhibiting atherosclerosis in these rabbits.  相似文献   

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We assessed the association between the haptoglobin (Hp) genotype and 2 common indicators of atherosclerotic plaque instability: macrophage infiltration and the smooth muscle cell (SMC) content. A total of 70 consecutive patients who underwent carotid endarterectomy were included in the study. For immunohistochemical study the anti-CD68 and anti-a-actin antibodies were used on adjacent serial sections; 36 plaques from patients with the Hp 1-1 or 2-1 genotype and 34 plaques from patients with the Hp 2-2 genotype were analyzed. The macrophage content (CD68+) was significantly higher in the Hp 2-2 group compared with that in the Hp 1-1 or 2-1 group (P < .001). In plaques from patients with diabetes, the SMC content was significantly lower in the Hp 2-2 group (P = .034). Carotid plaques from diabetic patients with Hp 2-2 genotype had higher macrophage infiltration and lower SMC content. Both parameters are indicators of atherosclerotic plaque instability.  相似文献   

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Progesterone is involved in various functions of the cardiovascular system, including those of vascular smooth muscle cells (VSMCs) via progesterone receptor (PR). Progesterone has also been postulated to be involved in inhibition of VSMC proliferation via PR. However, the details of PR expression have remained largely unknown in human cardiovascular VSMCs. Therefore, we first examined the relative levels of PR isoform (PR-A and PR-B) expression in VSMCs, using both immunohistochemistry and quantitative RT-PCR analysis. PR-B was equally expressed between male and female aorta, but PR-A was more abundant in female than in male aorta. This finding demonstrated that the status of PR subtype expression was associated with the difference of genders.  相似文献   

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Despite Fas expression, many cells resist Fas-induced apoptosis. Although differences in surface Fas expression can explain Fas resistance, multiple proteins below receptor level also inhibit Fas-induced apoptosis. To examine the mechanism of Fas resistance, we studied Fas-induced apoptosis in human medial vascular smooth muscle cells (VSMCs) from healthy coronary arteries. VSMCs showed marked heterogeneity to Fas-induced apoptosis, exhibiting both Fas-resistant (98.1+/-2.3% viable, n = 4, P = NS) and Fas-sensitive (31.3+/-2.6% viable, n = 3, P<0.01) cells. Fas-resistant VSMCs expressed surface Fas and could recruit RIP, indicating that functional receptor complexes were formed. However, Fas-resistant cells showed reduced expression of FADD, Fas ligand, and caspases 3, 7, and 8 and increased expression of FLIP and c-IAP-1. Fas-induced apoptosis was associated with cleavage of caspase 3 and blocked by inhibitors of caspase 3 or 8 but not caspase 1, 6, or 7. Selective inhibition of caspase 3 or 8 by antisense transfection inhibited Fas-induced apoptosis, but their reexpression could not rescue the Fas-resistant phenotype. In vivo, medial VSMCs showed marked heterogeneity of expression of caspase 3. We conclude that Fas sensitivity is determined not only by expression of surface Fas but by differential expression of Fas-signaling proteins below receptor level. Subpopulations of cells within the same tissue have different sensitivities to apoptosis, determined by expression of specific death-signaling proteins.  相似文献   

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Activin is a member of the transforming growth factor-beta superfamily, and it modulates the proliferation and differentiation of various target cells. In this study, we investigated the role of activin in the initiation and progression of human atherosclerosis. The expression of activin, its physiological inhibitor follistatin, and activin receptors were assayed in human vascular tissue specimens that represented various stages of atherogenesis. In situ hybridization experiments revealed activin mRNA in endothelial cells and macrophages and a strong induction of activin expression in neointimal smooth muscle cells from the early onset of atherogenesis. We developed an "in situ free-activin binding assay" by using biotinylated follistatin, which allowed us to detect bioactive activin at specific sites in atherosclerotic lesions. The mRNAs encoding the activin receptors are expressed similarly in normal and atherosclerotic tissue, which indicates that activin-A signaling in atherogenesis is most likely dependent on changes in growth factor concentrations rather than on receptor levels. In vitro, activin induces the contractile, nonproliferative phenotype in cultured smooth muscle cells, as is reflected by increased expression of smooth muscle-specific markers (SMalpha-actin and SM22alpha). Our data provide evidence that activin induces redifferentiation of neointimal smooth muscle cells, and we hypothesize that activin is involved in plaque stabilization.  相似文献   

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