基质金属蛋白酶-1，13及其抑制剂在急性冠脉综合征的作用及机制

基质金属蛋白酶-1，13（matrix metalloproteinase，MMP-1，13）能够降解胶原，在动脉粥样硬化斑块的特定区域的过度表达，可导致斑块基质的降解，从而导致斑块破裂，引发急性冠脉综合征（Acute coronary syndrome，ACS）。基质金属蛋白酶组织抑制因子（Tissue inhibitors of metalloproteinases，TIMPs）是MMPs内源性抑制系统，MMPs／TIMPs平衡失调可能是造成急性冠脉综合征发作的主要原因之一。     

西拉普利和缬沙坦对大鼠心肌梗死后心肌间质成分水平的干预研究

细胞外基质（ECM）是血管壁的主要成分，这些成分的合成和降解与动脉粥样硬化的发生发展密切相关，合成过多可造成血管狭窄，降解过多可诱发斑块破裂。心脏间质细胞（又称ECM成分）主要由Ⅰ型和Ⅲ型胶原构成的纤维网络组成，基质成分合成和降解的平衡受成纤维细胞分泌的基质金属蛋白酶（MMPs）和组织金属蛋白酶抑制剂（TIMPs）的调节。     

贝那普利对急性冠状动脉综合征患者血清基质金属蛋白酶9及C反应蛋白水平的影响

冠状动脉粥样硬化是冠心病的病理基础,炎症反应的活跃、基质金属蛋白酶（MMPs）活性增加可能是造成冠状动脉脉粥样斑块破裂的主要因素。MMPs是一类具有降解细胞外基质能力的内肽酶家族,基质金属蛋白酶9（matrix metallo proteinase 9,MMP-9）与动脉粥样硬化斑块的不稳定性尤为相关。C反应蛋白（C-reactive protein,CRP）作为经典的炎症标志物,其浓度的升高与急性冠状动脉综合征（ACS）的严重程度及预后密切相关。     

基质金属蛋白酶在冠心病研究中的进展

基质金属蛋白酶(MMPs)是一类依赖离子的含锌的内肽酶家族,可以降解细胞外基质(ECM)及基底膜中多种成分。在心血管疾病发生的病理及病理生理中,基质金属蛋白酶扮演者重要的角色。基质金属蛋白酶通过血管壁重塑、动脉粥样斑块的形成、不稳定斑块的形成、血管平滑肌细胞的迁移使血管狭窄,参与了冠心病的发生与发展。     

妊娠相关血浆蛋白A与急性冠脉综合征的关系研究进展

人体血管平滑肌细胞、细胞外基质、单核细胞和血管内皮细胞中均有妊娠相关血浆蛋白A表达,而且发现妊娠相关血浆蛋白A作为一种金属蛋白酶参与炎性反应,其外周血水平可反映动脉粥样硬化斑块炎症反应状态及其稳定性,动脉粥样硬化斑块内妊娠相关血浆蛋白A能促进纤维帽内胶原纤维和弹力纤维降解,破坏纤维帽结构,导致斑块破裂,继发血栓形成,造成冠状动脉血管腔完全或不完全阻塞,促使急性冠脉综合征的发生。     

基质金属蛋白酶与动脉粥样硬化斑块稳定性的关系研究进展

摹质金属蛋白酶(MMPs)是一组能够降解细胞外基质的酶类,可以通过加强动脉粥样硬化(As)斑块纤维骨架中胶原降解,影响斑块稳定性.目前研究认为,急性血管事件的发生与否主要取决于粥样斑块的稳定性,与血管的狭窄程度无直接关系[1].探讨影响斑块不稳定的因素,对避免急性心脑血管不良事件的发生有着重要意义.本文就MMPs与As不稳定斑块的相关性,及针对MMPs的应用做一综合分析.     

MMP-9、TIMP-1及hs-CRP与急性冠状动脉综合征的临床相关性研究

急性冠脉综合征（ACS）包括不稳定：心绞痛（UAP）、ST段抬高型和非盯段抬高型心肌梗塞（MI）,发病机制为冠状动脉粥样硬化易损斑块破裂及血栓形成,而炎症是导致冠脉易损斑块的形成和不稳定以及闭塞性血栓的重要原因。基质金属蛋白酶（Matrix metalloproteinases．MMPs）降解细胞外基质,是斑块破裂的核心因素。     

vWF：Ag和MMP-9水平检测在ACS斑块性质鉴别中的应用

动脉粥样硬化斑块的不稳定转化导致其破裂并发血栓形成,引起冠状动脉管腔急性严重阻塞或冠状动脉狭窄程度急剧加重,是急性冠状动脉综合征（ACS）的主要机制。血管性血友病因子（vWF）主要由血管内皮细胞合成,vWF升高是反映内皮细胞损伤的敏感指标,其对判断血栓形成的风险、病情轻重以及预后有重要意义。Brauner等研究认为基质金属蛋白酶-9（MMP-9）可以用于评价冠心病的严重程度,与患者斑块的稳定性有关。作者通过检测冠心病患者的血浆血管性血友病因子抗原（vWF：Ag）和MMP-9水平,探讨其变化特点,借此来判断斑块的稳定性,预测急性冠状动脉事件的发生。报道如下。     

冠状动脉粥样硬化斑块稳定性与超敏C反应蛋白和妊娠相关血浆蛋白A及基质金属蛋白酶组织抑制剂1表达的关系

目的:探讨冠心病患者血清非特异性炎性因子高敏C-反应蛋白、动脉粥样硬化稳定斑块中的妊娠相关血浆蛋白A及参与斑块破裂活动的基质金属蛋白酶3与冠状动脉粥样硬化斑块稳定性的关系。方法:选择2003-10/2004-03在解放军总医院住院治疗的70例冠心病患者为冠心病组,其中稳定心绞痛12例,不稳定心绞痛20例,发病6h内急性心肌梗死38例。对照组20人为健康体检者。均清晨空腹采肘静脉血5mL,离心分离血清后分为2份置-80℃,检测冠心病组和对照组的外周血血清高敏C反应蛋白、妊娠相关血浆蛋白A、基质金属蛋白酶3水平并进行相关性分析。结果:冠心病组70例及对照组20名均进入结果分析。①妊娠相关血浆蛋白A浓度比较:对照组低于稳定心绞痛组犤(0.7,1.1)mIU/L,(P<0.05)犦。②血清高敏C反应蛋白浓度比较:对照组明显低于不稳定心绞痛组犤(2.0,6.0)mg/L,(P<0.01)犦。③基质金属蛋白酶-3浓度比较:对照组明显低于急性心肌梗死组犤(48.5,63.6)ng/L,(P<0.01)犦。④冠心病患者3种不同类型的3项指标相关分析显示:血清高敏C反应蛋白水平与基质金属蛋白酶-3水平无相关性(r=0.099,P=0.539),与妊娠相关血浆蛋白A水平无相关性(r=0.017,P=0.210),血清基质金属蛋白酶3水平与妊娠相关血浆蛋白A水平有显著相关性(r=0.250,P=0.046)。结论:冠心病的发生与血清高敏C反应蛋白、妊娠相关血浆蛋白A、基质金属蛋白酶-3水平的变化相关联,而动脉粥样硬化斑块的不稳定只与妊娠相关血浆蛋白A及基质金属蛋白酶-3相关。     

心通口服液对冠心病心绞痛患者血清MMP-2、MMP-9的影响

冠心病心绞痛是指冠状动脉硬化或痉挛致管腔狭窄,使冠状动脉供血不足而导致的以心肌急剧的、暂时的缺血、缺氧为特征的临床综合征.随着人口的老龄化,它已成为严重危害人类身心健康的主要疾病之一[1].近年来研究表明基质金属蛋白酶(MMPs)与动脉粥样硬化斑块的破裂及由此导致的冠心病的发生、发展有关[2-3].2007年6月～2009年6月,作者采用酶联免疫吸附方法(ELISA法)检测了患者血清中基质金属蛋白酶2(MMP-2)和基质金属蛋白酶9(MMP-9)的表达,并用心通口服液对冠心病心绞痛患者进行干预,旨在探讨心通口服液对冠心病心绞痛的可能保护机制.     

Atherosclerosis]

Atherosclerosis is vascular disease characterized by thickening, hardening, and remodelling of the arterial wall. Occlusive vascular disease most often results from thrombosis superimposed on atherosclerotic plaque. Lipoproteins enter the vessel wall, promoting the recruitment of monocytes, which imbibe lipids and become foam cells. Smooth muscle cells invade these early plaques, producing connective tissue fibrils that form a fibrous cap over the lipid center; rupture of this cap is an important cause of thrombosis. The specific topography of early atherosclerotic lesions is primarily attributed to wall shear stress, one of hemodynamic forces. Inflammatory mediators regulate processes that determine the composition of the plaque's fibrous cap, a structure that separates blood from the thrombogenic lipid core. Factors involved in coagulation, such as thrombin, can regulate non-thrombotic functions of vascular wall cells such as smooth muscle proliferation or cytokine release. Tissue factor is a major regulator of coagulation and hemostasis. When the plaques are ruptured or eroded, exposure of cellular and extracellular tissue factor to circulating blood play a pivotal role in mediating fibrin-rich thrombus formation leading to acute coronary syndromes. Several serial angiographic studies have demonstrated that over 70% of acute coronary syndromes evolve from mildly to moderately obstructive atherosclerotic plaques.     

Definition and pathophysiology of acute coronary syndrome

Acute coronary syndrome is a clinical state induced by the thrombosis following the rupture of unstable atherosclerotic plaque. Atherosclerotic plaque increases its vulnerability by the accumulation of foam cells, inflammation, oxidative stress, and apoptosis of vascular wall cells including macrophage. Inflammation and oxidative stress stimulates macrophages to produce matrix metalloproteinase (MMP), which degrades extracellular matric proteins and causes thinning of the fibrous cap. When the fibrous cap of the plaque tears, thrombogenic lipid core is exposed to blood, and platelets accumulate at the site, resulting in the significant reduction of coronary blood flow. Treatment of acute coronary syndrome patients should be focused on the stabilization of the plaque as well as vasodilatation, oxygen supply, or control of hemodynamics.     

Imaging of the vulnerable plaque: new modalities

Atherosclerosis is currently considered to be an inflammatory and thus a systemic disease affecting multiple arterial beds. Recent advances in intravascular imaging have shown multiple sites of atherosclerotic changes in coronary arterial wall. Traditionally, angiography has been used to detect and characterize atherosclerotic plaque in coronary arteries, but recently it has been found that plaques that are not significantly stenotic on angiography cause acute myocardial infarction. As a result, newer imaging and diagnostic modalities are required to predict which of the atherosclerotic plaque are prone to rupture and hence distinguish "stable" and "vulnerable" plaques. Intravascular ultrasound can identify multiple plaques that are not seen on coronary angiography. Thermography has shown much promise and is based on the concept that the inflammatory plaques are associated with increased temperature and can also identify "vulnerable patients." Of all these newer modalities, magnetic resonance imaging has shown the most promise in identification and characterization of vulnerable plaques. In this article, we review the newer coronary artery imaging modalities and discuss the limitations of traditional coronary angiography.     

Relationship between non-alcoholic fatty liver disease and coronary heart disease

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and considered a liver manifestation of metabolic syndrome. It is in close relationship with insulin resistance, obesity, diabetes mellitus, all of which increase risk of cardiovascular disease (CVD). Besides, many studies point out that NAFLD independently contributes to the development of atherosclerosis and CHD. On the other hand, CVDs are the leading cause of death in NAFLD patients. Many pathophysiological changes and molecular mechanisms play an important role in NAFLD for CVD formation. Atherosclerosis is common in NAFLD, which also mainly contributes to the CVD formation and CHD. Many studies linking atherosclerotic CHD and NAFLD are present in the literature. Subclinical CHD, mainly detected by coronary computed tomography views, have been detected more common in NAFLD patients. Presence of NAFLD has been found to be more common in patients with severe CHD and in stable CHD, NAFLD has been found to be associated with more diffuse disease. In acute coronary syndromes, especially in acute myocardial infarction, patients with NAFLD have been found to have poor prognosis when compared with NAFLD free patients. In this review, our aim is to evaluate the relationship between NAFLD and CHD in detail and go over the pathophysiological mechanisms underlying this relationship.     

Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice

The majority of acute clinical manifestations of atherosclerosis are due to the physical rupture of advanced atherosclerotic plaques. It has been hypothesized that macrophages play a key role in inducing plaque rupture by secreting proteases that destroy the extracellular matrix that provides physical strength to the fibrous cap. Despite reports detailing the expression of multiple proteases by macrophages in rupture-prone regions, there is no direct proof that macrophage-mediated matrix degradation can induce plaque rupture. We aimed to test this hypothesis by retrovirally overexpressing the candidate enzyme MMP-9 in macrophages of advanced atherosclerotic lesions of apoE-/- mice. Despite a greater than 10-fold increase in the expression of MMP-9 by macrophages, there was only a minor increase in the incidence of plaque fissuring. Subsequent analysis revealed that macrophages secrete MMP-9 predominantly as a proform, and this form is unable to degrade the matrix component elastin. Expression of an autoactivating form of MMP-9 in macrophages in vitro greatly enhances elastin degradation and induces significant plaque disruption when overexpressed by macrophages in advanced atherosclerotic lesions of apoE-/- mice in vivo. These data show that enhanced macrophage proteolytic activity can induce acute plaque disruption and highlight MMP-9 as a potential therapeutic target for stabilizing rupture-prone plaques.     

Usefulness of coronary angioscopy for the evaluation of hyperlipidemia

Hyperlipidemia is one of the major coronary risk factors, which leading to the clinical worse outcome in patients with coronary artery disease, that is, acute coronary syndrome. Coronary plaque rupture followed by the formation of thrombus has been revealed to be a major cause of acute coronary syndrome. It would be important to detect the vulnerable plaque before its rupture, but there were no ways to detect by the conventional methods except coronary angioscopy. Yellow plaque and thrombus are mostly observed at the culprit lesion by the coronary angioscopy, which suggests that vulnerable plaque is dark yellow. Coronary angioscopy may diagnose the high-risk group among patients with hyperlipidemia.     

磁共振评估冠状动脉粥样硬化斑块的研究进展

冠状动脉粥样硬化性心脏病(coronary atherosclerosis heart disease,CHD)是人类主要死亡原因之一,其中急性冠脉综合征(acute coronary syndromes,ACS)是导致患者预后不良和发生猝死的主要原因。尸检病理结果发现,ACS发病的主要原因为动脉粥样硬化易损斑块破裂或内皮表面糜烂导致冠脉内血栓形成。磁共振成像(magnetic resonance imaging,MRI)作为一种无创、可重复性强、组织分辨率高的检查方法,多对比成像序列经过20余年的研发在颈动脉粥样硬化斑块中的应用已得到广泛证实,并在临床上及病理对照上得到进一步的验证。但冠状动脉管壁成像由于成像技术复杂,目前尚处于研究阶段。本文就磁共振成像评估冠状动脉粥样硬化斑块的研究进展进行综述。     

Use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in patients with acute coronary syndrome

Renin-angiotensin system is well known that it plays an important role in the initiation and amplification of atherosclerosis that lead to cardiovascular disease. Angiotensin II is deeply involved in vasoconstriction, oxidative stress, inflammation, thrombosis, vascular remodeling, and sympathetic nerve activity. Many studies have documented the favorable effects of angiotensin converting enzyme inhibitor(ACE-I) and angiotensin receptor blocker(ARB) on cardiovascular disease in basic and clinical trials. Now accumulated evidences suggest ACE-I and ARB potentially prevent coronary plaque rapture, thrombosis and myocardial remodeling with acute coronary syndrome (ACS). ACS is occurred from plaque rupture on mild to moderate coronary atherosclerosis. Therefore, on treatment of ACS, it is important to prevent the plaque rupture and thrombosis by pharmacological intervention with ACE-I and ARB than coronary artery intervention which is down stream therapy for coronary artery stenosis.     

MRI of vulnerable plaque

Atherosclerosis is a systemic inflammatory disease resulting in vascular complications such as myocardial infarction or stroke. Noninvasive imaging of early stages of this systemic disease could help guide early interventional or medical therapies. Molecular targeting with MRI using epitope-specific contrast agents has proven to be effective in detection of different stages of atherosclerosis, beginning with an endothelial dysfunction and ending in plaque rupture with superimposed thrombosis. Animal models of atherosclerosis and thrombosis in combination with molecular imaging can help us to understand more about disease progression, therapeutic impact, and molecular mechanisms. This article reviews recent developments in molecular MRI concerning atherosclerosis, highlighting the vulnerable plaque as a key structure of plaque pathology.