老年冠心病患者的颈动脉超声特征与胆红素血脂综合指数、斑块稳定性的相关性分析

摘要 目的：探讨老年冠心病患者的颈动脉超声特征与胆红素血脂综合指数、斑块稳定性的相关性。方法：选择2021年1月至2022年12月来我院诊治的冠心病患者120例。检测所有患者的TC、LDL-C、HDL-C、TBIL、血清I型前胶原羧基端前肽、组织蛋白酶K、基质金属蛋白酶-1、基质金属蛋白酶-9水平,并行颈动脉超声进行检查,确定颈动脉内膜中层厚度,同时行冠状动脉造影,确定冠状动脉病变支数及冠状动脉病变积分。分析不同冠状动脉病变组的颈动脉块数、颈总动脉的超声血流参数及生化指标水平,分析不同颈动脉内膜中层厚度患者的生化指标水平,分析不同冠状动脉病变积分患者的生化指标水平,分析120例冠心病患者颈动脉超声特征及胆红素血脂综合指数、血清斑块稳定性指标的相关性。结果：三支病变组的颈动脉内膜中层厚度、Gokmen积分、TC/（HDL-C+TBIL）、LDL-C/（HDL-C+TBIL）、I型前胶原羧基端前肽、组织蛋白酶K、基质金属蛋白酶-1、基质金属蛋白酶-9水平明显较单支及双支病变组高,双支病变组的以上指标明显较单支病变组高（P均<0.05）,单病变组的TBIL明显较双支及三支高（P<0.05）,其在双支及三支病变组间无统计学意义（P>0.05）。内膜正常组的TC/（HDL-C+TBIL）、LDL-C/（HDL-C+TBIL）、I型前胶原羧基端前肽、组织蛋白酶K、基质金属蛋白酶-1、基质金属蛋白酶-9水平明显较内膜增厚组及斑块形成组高,内膜增厚组以上指标明显较斑块形成组高（P均<0.05）,内膜正常组的TBIL明显较内膜增厚组与斑块形成组高（P<0.05）,而内膜增厚组与斑块形成组间对比无统计学意义（P>0.05）。冠状动脉病变积分≤5分组的TC/（HDL-C+TBIL）、LDL-C/（HDL-C+TBIL）、I型前胶原羧基端前肽、组织蛋白酶K、基质金属蛋白酶-1、基质金属蛋白酶-9水平明显较6~10分组及11~15分组高,6~10分组以上指标明显较11~15分组高（P均<0.05）,≤5分组的TBIL明显较6~10分组与11~15分组高（P<0.05）,而在6~10分组与11~15分组间对比无差异（P>0.05）。不同组间的TC、LDL-C、HDL-C水平对比无统计学意义（P>0.05）。颈动脉内膜中层厚度、Gokmen积分与TC/（HDL-C+TBIL）、LDL-C/（HDL-C+TBIL）、I型前胶原羧基端前肽、组织蛋白酶K、基质金属蛋白酶-1、基质金属蛋白酶-9水平均呈正比（P<0.05）;颈动脉内膜中层厚度、Gokmen积分与TC、LDL-C、HDL-C、TBIL水平无相关性（P>0.05）。结论：老年冠心病患者的冠状动脉病变越严重,其颈动脉超声特征、胆红素血脂综合指数、斑块稳定性不断恶化,颈动脉超声特征指标与胆红素血脂综合指数、斑块稳定性指标水平呈正相关。     

急性脑梗死患者颈动脉斑块与基质金属蛋白酶、血清白介素及多肽生长因子的关系研究

目的:探讨基质金属蛋白酶、血清白介素及多肽生长因子与急性脑梗死患者颈动脉斑块的关系。方法:选取于2017年1月至2017年12月期间北京中医药大学第三附属医院老年病科收治的60例急性脑梗死患者作为观察组,根据彩色多普勒超声检测仪进行颈动脉超声检查,将结果分为无斑块组(20例),稳定斑块组(20例)和不稳定斑块组(20例),选取同期的60例门诊体检健康者作为对照组。采用双抗体夹心酶标免疫吸附法(ELISA)测定血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18以及血清多肽生长因子VEGF和TGF-β1水平,对观察组及对照组的检测结果以及无斑块组、稳定斑块组、不稳定斑块组及对照组的检测结果进行分析研究。结果:观察组的血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18水平以及血清多肽生长因子VEGF水平显著高于对照组,差异有统计学意义(P0.05),观察组的血清多肽生长因子TGF-β1水平则显著低于对照组,差异有统计学意义(P0.05)。稳定性斑块组体质指数显著高于对照组(P0.05);不稳定性斑块组与对照组相比,BMI、TC及TG水平均显著升高(P0.05),且与无斑块组相比,甘油三酯水平也偏高(P0.05)。无斑块组,稳定斑块组及不稳定斑块组的血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18水平以及血清多肽生长因子VEGF和TGF-β1水平比较,差异有统计学意义(P0.05),其中除血清多肽生长因子TGF-β1水平显著低于其它2组外,不稳定斑块组的血清基质金属蛋白酶MMP-7、MMP-9、MMP-12水平,血清白介素IL-6、IL-8、IL-18水平以及血清VEGF水平显著高于其它2组,差异有统计学意义(均P0.05)。结论:急性脑梗死患者的血清基质金属蛋白酶、血清白介素以及血清多肽生长因水平与颈动脉斑块密切相关。     

阿斯匹林对T H P-1来源巨噬细胞M M P g的表达及其活性的影响

目的：探讨阿司匹林对基质金属蛋白酶9（Matrix Metalloproteinases,MMPs）表达及其活性的影响。方法：应用MTT法观察阿司匹林对THP-1来源巨噬细胞增殖的影响;逆转录聚合酶链反应检测阿司匹林对体外培养的THP-1细胞基质金属蛋白酶9mRNA表达的影响,应用明胶酶谱法观察阿司匹林对体外培养的THP-1来源巨噬细胞基质金属蛋白酶9活性的影响。结果：与对照组相比,不同浓度的阿司匹林（150、3000、600、1200μmol／l）对THP-1采源巨噬细胞增殖无影响;不同浓度的阿司匹林可以抑制PMA诱导的THP-1细胞基质金属蛋白酶9mRNA的水平及其活性水平,且呈浓度依赖性。结论：阿司匹林可以抑制PMA诱导的THP-1巨噬细胞基质金属蛋白酶9的表达,并可能通过这一机制影响动脉粥样硬化斑块的稳定性．     

骨关节炎患者血清中基质金属蛋白酶-2、-9的明胶酶谱分析

为探讨基质金属蛋白酶-2、-9在骨关节炎发病中的作用,应用明胶酶谱分析方法研究其在骨关节炎患者血清中的表达水平。实验对象为27例膝骨关节炎患者,对照组为7例外伤骨折患者。结果发现病例组血清中基质金属蛋白酶-2和-9的表达水平均明显高于对照组(P<0.05)。该结果显示基质金属蛋白酶-2和-9可能在骨关节炎的发病过程中均起着重要的作用。     

基质金属蛋白酶

基质金属蛋白酶是一类分解细胞外基质组分的锌蛋白酶⒚它们在有机体生长发育中的细胞外基质逆转与重塑以及疾病中的病理损害起着极为重要的作用⒚基质金属蛋白酶的表达和活性在不同细胞水平受到严密调控,如细胞因子、生长因子以及激素的调节⒚基质金属蛋白酶以酶原形式分泌,随后被其它蛋白酶如胞浆素或非蛋白酶类化学物质如有机汞所激活⒚所有基质金属蛋白酶都受到天然抑制剂 金属蛋白酶组织抑制剂所抑制⒚两者的不平衡导致许多疾病的发生,如肿瘤侵入及转移⒚合成基质金属蛋白酶组织抑制剂所抑制,如 Ｍ ａｒｉｍ ａｓｔａｔ 能控制肿瘤转移的发生及进一步扩散⒚本文将对基质金属蛋白酶的特征、分子区域结构、底物特性、激活机制、调控方式等方面进行最新概述⒚     

CD147、基质金属蛋白酶与动脉粥样硬化

CD147分子是细胞外基质金属蛋白酶（MMP）的诱导剂,在多种肿瘤细胞和组织中高表达,通过诱导MMP的分泌促进肿瘤的侵袭和转移。MMP在动脉粥样硬化的发生、发展和斑块破裂等心血管并发症的发生中起重要作用。论述了粥样斑块中CD147的表达、CD147对MMP的调控,以及MMP活化对斑块的形成、破裂、引发心肌梗死等急性心血管事件的关联性。     

基质金属蛋白酶与心肌重塑

细胞外基质参与和促进了心肌重塑的过程,基质金属蛋白酶是调节细胞外基质重要的酶,基质金属蛋白酶在心肌重塑过程表达变化可分为三个时相,其活性受到信号传导途径、炎症因子和活性氧/活性氮的调节,基质金属蛋白酶可能作为心肌梗塞等疾病治疗的靶标     

基质金属蛋白酶-9与动脉粥样硬化

基质金属蛋白酶-9（matrix metalloproteinase 9,MMP-9）是基质金属蛋白酶家族中的一种,通过降解胞外基质．在动脉粥样硬化的血管重构、斑块不稳定所导致的心血管病的发展过程中发挥着重要的作用。     

基质金属蛋白酶检测技术的研究进展

基质金属蛋白酶是降解细胞外基质的重要酶类。在正常生理状态下,基质金属蛋白酶参与新生血管的形成及伤口的愈合;在病理状态下它参与组织重构、恶性肿瘤转移等病理进程。通过对基质金属蛋白酶检测,可以深度了解其性质及致病机理,并进一步了解病症的恶化程度,从而进行及时检测治疗。现根据基质金属蛋白酶的功能及特性,对基质金属蛋白酶活性和表达两大方面的检测技术进行了综述,为研究人员选择合适的基质金属蛋白酶检测技术提供参考。     

基质金属蛋白酶及其抑制剂在乳腺癌中的表达

目的:研究基质金属蛋白酶2(Matrix Metalloproteinase-2,MMP-2),基质金属蛋白酶7(MMP-7),基质金属蛋白酶9(MMP-9),膜型基质金属蛋白酶(Membrane Type-1 Matrix Metalloproteinase,MT1-MMP),金属蛋白酶组织抑制剂1(Tissue Inhibitor of Metalloproteinase,TIMP-1),金属蛋白酶组织抑制剂2(TIMP-2)在乳腺癌组织中mRNA的表达,及与临床病理变量之间的关联。方法:采用150例乳腺癌患者的组织样本。使用半定量逆转录-聚合酶链反应(RT-PCR)法来测定肿瘤组织和正常乳腺组织中MMP-2,MMP-7,MMP-9,MT1-MMP,TIMP-1和TIMP-2的mRNA表达。结果:MMP-2,MMP-7,MMP-9,MT1-MMP,TIMP-1和TIMP-2在乳腺癌中的mRNA表达显著高于正常组织。结论:MMP-2,MMP-7,MMP-9,和MTI-MMP的表达增加和临床病理参数之间的关联,可以用来预测乳腺癌的侵害行为。     

Specific Matrix Metalloproteinases Play Different Roles in Intraplaque Angiogenesis and Plaque Instability in Rabbits

Background

Ectopic angiogenesis within the intima and media is considered to be a hallmark of advanced vulnerable atherosclerotic lesions. Some studies have shown that specific matrix metalloproteinases (MMPs) might play different roles in angiogenesis. Therefore, we investigated the predominant effects of specific MMPs in intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis.

Methods and Results

New Zealand rabbits underwent balloon injury of the abdominal artery and ingestion of a high-cholesterol (1%) diet to establish an atherosclerotic animal model. At weeks 4, 6, 8, 10, and 12 after balloon injury, five rabbits were euthanized and the abdominal aorta was harvested. Blood lipid analysis, intravascular ultrasound imaging, pathologic and immunohistochemical expression studies, and western blotting were performed. From weeks 4 to 12, the expression of MMP-1, -2, -3, and -9 and vascular endothelial growth factor A (VEGF-A) increased with atherosclerotic plaque development in the abdominal aorta, while the expression of MMP-14 substantially decreased. The vulnerability index (VI) gradually increased over time. Intraplaque neovessels appeared at week 8. The microvessel density (MVD) was greater at week 12 than at week 8. The VI, MVD, and VEGF-A level were positively correlated with the MMP-1, -2,-3, and -9 levels within plaques. Negative correlations were noted between the MMP-14 level and the VI, MVD, and VEGF-A level.

Conclusion

Upregulation of MMP-1, -2, -3, and -9 and downregulation of MMP-14 may contribute to intraplaque angiogenesis and plaque instability at the advanced stage of atherosclerosis in rabbits.     

Overexpression of CXCL16 promotes a vulnerable plaque phenotype in Apolipoprotein E-Knockout Mice

BackgroundCXCL16 has been shown to be involved in atherosclerotic lesion development, but its role in preexisting lesions is still unclear. This study aims to assess the effect of CXCL16 on the stability of preexisting lesions.MethodsWe firstly measured plasma CXCL16 level in Apolipoprotein E–Knockout (ApoE KO) mice with either high-cholesterol diet (HCD) or normal diet (ND) by enzyme-linked immunosorbent assay (ELISA). Then, silastic collars were placed around the carotid arteries in HCD-ApoE KO mice to accelerate atherosclerotic lesions. Five weeks later, CXCL16 was overexpressed by intravenous injection of lentivirus carrying CXCL16 transgene. Two weeks after infection, lesions were stained with hematoxylin and eosin (HE) and with oil red O. Biomarkers in the lesions, such as MMPs, CCL2, VCAM-1 and TNF-α were measured by real-time polymerase chain reaction (RT-PCR), which indicate the instability of plaques.ResultsThe level of CXCL16 in plasma was higher in HCD-ApoE KO mice as compared to ND-ApoE KO mice. Circulating CXCL16 overexpression does not affect the size of preexisting plaques, but it leads to vulnerable plaque morphology and increases the expression of markers of plaque destabilization.ConclusionSystemic CXCL16 becomes much higher in atherosclerosis, and it could be a potential atherogenic biomarker. Overexpression of CXCL16 promotes the evolution of preexisting lesions to vulnerable plaques in ApoE KO mice.     

Increased Production of Matrix Metalloproteinases in Enriched Astrocyte and Mixed Hippocampal Cultures Treated with β-Amyloid Peptides

Abstract: Growing evidence supports the notion of a functional relationship between the presence of the β-amyloid (Aβ) peptide and the production of inflammatory mediators in and around neuritic plaques of Alzheimer's disease. Tissue remodeling enzymes that are critical in peripheral inflammatory responses are the matrix metalloproteinases (MMPs), enzymes produced by neurons and glia. Thus, it was of interest to determine whether Aβ may alter the expression of MMPs in glial and neuronal cultures. It was demonstrated that Aβ (1–40) is a potent stimulator of MMP-9 and MMP-2 activity in addition to inducing the expression of a lower molecular weight, unidentified gelatinase activity in mixed hippocampal and astrocyte cultures. Shorter fragments of Aβ were less effective in stimulating the production of these enzymes. The lower molecular weight activity was observed only in response to Aβ, and not after treatment with various cytokines. In addition, both cultures express MMP-3 (stromelysin-1) in response to Aβ peptides. These results suggest that MMPs may play a role in the development or progression of neuritic plaques, i.e., abnormal neurite outgrowth.     

Metalloproteinases promote plaque rupture and myocardial infarction: A persuasive concept waiting for clinical translation

Atherosclerotic plaque rupture provokes most myocardial infarctions. Matrix metalloproteinases (MMPs) have counteracting roles in intimal thickening, which stabilizes plaques, on the one hand and extracellular matrix destruction that leads to plaque rupture on the other. This review briefly summarizes the key points supporting the involvement of individual MMPs in provoking plaque rupture and discusses the barriers that stand in the way of clinical translation, which can be itemised as follows: structural and functional complexity of the MMP family; lack of adequate preclinical models partly owing to different expression patterns of MMPs and TIMPs in mouse and human macrophages; the need to target individual MMPs selectively; the difficulties in establishing causality in human studies; and the requirement for surrogate markers of efficacy. Overcoming these barriers would open the way to new treatments that could have a major impact on cardiovascular mortality worldwide.     

Expanding expression of the 5-lipoxygenase/leukotriene B4 pathway in atherosclerotic lesions of diabetic patients promotes plaque instability

Emerging evidence now indicates that the 5-lipoxygenase (5-LO) pathway play a role in the pathogenesis of atherosclerosis and restenosis. The expression of 5-LO by activated macrophages in symptomatic plaques leads to leukotriene B(4) (LTB(4)) accumulation and enhanced synthesis and release of matrix metalloproteinases (MMPs) that can promote plaque rupture. However, the role of 5-LO pathway in diabetic vascular disease has not been previously reported. Thus, the present study was designed to analyze the expression of 5-LO in carotid plaques of diabetic patients and to investigate the possible role of 5-LO pathway in the pathogenesis and progression of diabetic atherosclerosis. Atherosclerotic plaques from 60 patients undergoing carotid endarterectomy were divided into non-diabetic and diabetic group. Plaques were analyzed for 5-LO, MMP-2 and MMP-9 by immunohistochemical, Western blot, and densitometric analyses, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+macrophages, CD3+T-lymphocytes, and HLA-DR+inflammatory cells. LTB(4) were quantified by enzyme-linked immunosorbent assay. 5-LO showed abundant immunoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage infiltrates in atherosclerotic intima. 5-LO expression was higher in diabetic compared with non-diabetic plaques and was associated with increased MMP-2 and MMP-9 expression. Follow-up analyze with zymography assay revealed MMP activity was elevated in diabetic compared with non-diabetic plaques. Notably, in contrast to non-diabetic plaques, LTB(4) levels were significantly increased in diabetic plaques by enzyme-linked immunosorbent assay. These results suggest that overexpression of 5-LO and LTB(4) in atherosclerotic plaques possibly promote MMP-induced plaque rupture in diabetes. Hence, anti-LTs may be useful, not only in reducing atherogenesis, but also in the prevention and treatment of acute atherothrombotic events in diabetic patients.     

Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension.

The aim of the work was to analyze, on a comparative basis, the signaling pathways operating in the regulation of a panel of matrix metalloproteinases (MMP) expressed by human dermal fibroblasts submitted to mechanical stress relaxation by cytochalasin D (CD) and in a retracting collagen gel (RCG). The mRNA steady-state level of MMPs was measured by a quantitative RT-PCR procedure using a synthetic RNA as internal standard. In monolayer, most MMPs were barely detected, except MMP-2. Disruption of the actin stress fibers by CD induced a moderate increase of MMP-2 mRNA and a much larger stimulation of MMP-3, -9, -13 and -14 mRNAs. In RCG, a significant up-regulation of these MMPs was also observed although to a lower extent than in CD-treated monolayers. Among the investigated MMPs, the MMP-8 and -11 were not reproducibly detected. MMP-2 was processed to its active form both by CD and in RCG. The CD-induced up-regulation of gene expression was largely repressed by blocking protein synthesis by cycloheximide for all the MMPs, by inhibiting the tyrosine-kinases of the src family by herbimycin A for all MMPs, except MMP-2, and by inhibiting the TPA-inducible PKC isoforms by bisindoyl maleimide for all MMPs, except MMP-14. The up-regulation induced by stress relaxation in RCG was protein synthesis-dependent for MMP-2 and MMP-13, tyrosine kinases-dependent for MMP-3 and MMP-13, as previously described for MMP-1. Inhibiting TPA-inducible PKC did not affect any MMP in RCG except MMP-13, which was strongly induced. The processing of MMP-2 was tyrosine kinases-dependent but PKC-independent. Inhibitors of the ERK1,2 and p38 MAP kinases pathways diversely affected the MMPs expression. Inhibiting the Rho-kinase activity by Y-27632 was inactive. These results point to the potent regulation operated by the status of the cytoskeleton on the cell phenotype, and to distinct regulatory pathways involved in the control of different MMPs expression.     

Functional roles of the tissue inhibitor of metalloproteinase 3 (TIMP-3) during ascorbate-induced differentiation of osteoblastic MC3T3-E1 cells

The tissue inhibitor of the metalloproteinase-3 (TIMP-3) gene was isolated as a gene involved in the process of ascorbate-induced differentiation of mouse MC3T3-E1 cells by the differential display method. The functional roles of TIMP-3 were characterized by establishing stable cell lines, which constitutively expressed the TIMP-3 gene. The TIMP-3 transfectants produced type I collagen at the same level as that of normal cells in response to ascorbic acid 2-phosphate (AscP). However, the expression of the other osteoblastic marker proteins such as alkaline phosphatase (ALPase), osteopontin (OP), osteocalcin (OC), osteonectin (ON) and matrix metalloproteinases (MMPs) remained at a low level even in the presence of AscP. Furthermore, no mineralization of the extracellular matrix (ECM) occurred with the transfectants. Remodeling ECM through TIMPs and MMPs is concluded to be required for osteoblastic differentiation.     

Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF‐κB pathway

Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and nitric oxide induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analysed for bFGF, FGF‐receptors‐1 and ‐2 (FGFR‐1/‐2), inducible nitric oxide synthase (iNOS) and MMP‐9 expression. Our data revealed increased expression of bFGF and FGFR‐1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP‐9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up‐regulation of both iNOS and MMP‐9 that was specifically mediated by nuclear factor‐κB (NF‐κB) activation. Collectively, our data demonstrate a novel NF‐κB‐mediated pathway linking bFGF with iNOS and MMP‐9 expression that is associated with carotid plaque vulnerability.