The accumulation of specific types of proteoglycans in eroded plaques: a role in coronary thrombosis in the absence of rupture

PURPOSE OF REVIEW: Although fibrous cap rupture is the primary cause of coronary thrombosis, plaque erosion is responsible for 30%-40% of acute thrombotic events. The interface of the eroded surface involves a denuded endothelium allowing direct contact of the platelet/fibrin thrombus with the underlying lesion. This review discusses the putative role of extracellular matrix molecules, in particular proteoglycans/hyaluronan, in the development of acute coronary thrombosis associated with erosion. RECENT FINDINGS: The plaque/thrombus interface in erosion presents a unique surface since it consists of predominantly SMCs and proteoglycans with minimal or no inflammation. The lack of significant inflammation raises the possibility that erosion represents chronic wounding rather than true atherogenesis. The abundance of proteoglycan and hyaluronan matrix suggests their potential role in the development of thrombosis. Matrix changes may contribute to endothelial loss, the magnitude of the thrombotic event, or both. Versican facilitates platelet adhesion at low shear and cooperates with collagen to promote platelet aggregation. Further, versican may, in part, regulate water content and in turn support coagulation because water-dependent functionality of anticoagulation molecules. Finally, experimental models of plaque erosion are currently being developed guided by the premise that the loss of surface endothelium together with other procoagulant factors may underlie the development of platelet-rich thrombi. SUMMARY: The loss of endothelium and exposure of a potentially procoagulant versican-hyaluronan matrix may be largely responsible for plaque erosion. The development of relevant animal models should allow further insight into the pathophysiology of coronary thrombosis in the absence of rupture.     

Do metalloproteinases destabilize vulnerable atherosclerotic plaques?

PURPOSE OF REVIEW: Atherosclerotic plaque rupture and thrombosis underlie most myocardial infarctions. Matrix metalloproteinases are a family of enzymes that remodel the extracellular matrix. Metalloproteinases could stabilize rupture-prone plaques by promoting smooth muscle cell migration and proliferation. Alternatively, metalloproteinases could destabilize vulnerable plaques by promoting matrix destruction, angiogenesis, leucocyte infiltration, and apoptosis. Evidence is reviewed from genetically modified mice and human biomarker and genetic studies that sheds light on this dual role of metalloproteinases. RECENT FINDINGS: Inhibition of metalloproteinases in mice using tissue inhibitors of metalloproteinases increases plaque stability; however, double knockouts of apolipoprotein E with matrix metalloproteinase 2, 3, 7, 9, 12, and 13 have more or less stable plaques, consistent with harmful or protective effects of individual metalloproteinases. Overexpression studies in mice or rabbits show that high activities of matrix metalloproteinase 9 and 12 decrease stability. Biomarker and human genetic studies demonstrate that increased metalloproteinase activity is associated with vascular repair or myocardial infarction. SUMMARY: Recent studies reinforce evidence for a dual role of matrix metalloproteinases in plaque stabilization and rupture, which probably depends on the stage, site, and severity of disease. Dysregulated metalloproteinase activity in end-stage coronary artery disease appears a valid target for therapy.     

DNA甲基化调控炎症反应干预As斑块稳定性的研究进展

动脉粥样硬化(As)斑块破裂是导致急性心脑血管事件发生的首要原因。既往对斑块破裂的基础研究多集中于细胞和分子水平,从表观遗传学角度阐述的研究较少。DNA甲基化作为表观遗传学修饰的主要方式之一,可在不改变基因核苷酸序列的情况下影响基因的表达。综合目前研究来看,炎症反应在斑块破裂过程中起关键性作用,而DNA甲基化对炎症反应又起重要的调控作用。因此,改变DNA甲基化状态来调控炎症反应干预As斑块稳定性,有望成为防治As等心脑血管疾病的有效途径之一。本文主要围绕与As炎症反应密切相关的几种炎症免疫细胞及炎症因子等方面,对近年来DNA甲基化调控炎症反应干预As斑块稳定性的研究进展作一综述。     

Local critical stress correlates better than global maximum stress with plaque morphological features linked to atherosclerotic plaque vulnerability: an in vivo multi-patient study

Background  

It is believed that mechanical stresses play an important role in atherosclerotic plaque rupture process and may be used for better plaque vulnerability assessment and rupture risk predictions. Image-based plaque models have been introduced in recent years to perform mechanical stress analysis and identify critical stress indicators which may be linked to rupture risk. However, large-scale studies based on in vivo patient data combining mechanical stress analysis, plaque morphology and composition for carotid plaque vulnerability assessment are lacking in the current literature.     

ACE inhibition and atherogenesis

Recent clinical studies such as HOPE, SECURE, and APRES show that angiotensin-converting enzyme (ACE) inhibitors like ramipril improve the prognosis of patients with a high risk of atherothrombotic cardiovascular events. Atherosclerosis, as a chronic inflammatory condition of the vascular system, can turn into an acute clinical event through the rupture of a vulnerable atherosclerotic plaque followed by thrombosis. ACE inhibition has a beneficial effect on the atherogenic setting and on fibrinolysis. Endothelial dysfunction is the end of a common process in which cardiovascular risk factors contribute to inflammation and atherogenesis. By inhibiting the formation of angiotensin II, ACE inhibitors prevent any damaging effects on endothelial function, vascular smooth muscle cells, and inflammatory vascular processes. An increase in the release of NO under ACE inhibition has a protective effect. Local renin-angiotensin systems in the tissue are involved in the inflammatory processes in the atherosclerotic plaque. Circulating ACE-containing monocytes, which adhere to endothelial cell lesions, differentiate within the vascular wall to ACE-containing macrophages or foam cells with increased local synthesis of ACE and angiotensin II. Within the vascular wall, angiotensin II decisively contributes to the instability of the plaque by stimulating growth factors, adhesion molecules, chemotactic proteins, cytokines, oxidized LDL, and matrix metalloproteinases. Suppression of the increased ACE activity within the plaque can lead to the stabilization and deactivation of the plaque by reducing inflammation in the vascular wall, thus lessening the risk of rupture and thrombosis and the resultant acute clinical cardiovascular events. The remarkable improvement in the long-term prognosis of atherosclerotic patients with increased cardiovascular risk might be the clinical result of the contribution made by ACE inhibition in the vascular wall.     

Relation between TLR4/NF‐κB signaling pathway activation by 27‐hydroxycholesterol and 4‐hydroxynonenal,and atherosclerotic plaque instability

It is now thought that atherosclerosis, although due to increased plasma lipids, is mainly the consequence of a complicated inflammatory process, with immune responses at the different stages of plaque development. Increasing evidence points to a significant role of Toll‐like receptor 4 (TLR4), a key player in innate immunity, in the pathogenesis of atherosclerosis. This study aimed to determine the effects on TLR4 activation of two reactive oxidized lipids carried by oxidized low‐density lipoproteins, the oxysterol 27‐hydroxycholesterol (27‐OH) and the aldehyde 4‐hydroxynonenal (HNE), both of which accumulate in atherosclerotic plaques and play a key role in the pathogenesis of atherosclerosis. Secondarily, it examined their potential involvement in mediating inflammation and extracellular matrix degradation, the hallmarks of high‐risk atherosclerotic unstable plaques. In human promonocytic U937 cells, both 27‐OH and HNE were found to enhance cell release of IL‐8, IL‐1β, and TNF‐α and to upregulate matrix metalloproteinase‐9 (MMP‐9) via TLR4/NF‐κB‐dependent pathway; these actions may sustain the inflammatory response and matrix degradation that lead to atherosclerotic plaque instability and to their rupture. Using specific antibodies, it was also demonstrated that these inflammatory cytokines increase MMP‐9 upregulation, thus enhancing the release of this matrix‐degrading enzyme by macrophage cells and contributing to plaque instability. These innovative results suggest that, by accumulating in atherosclerotic plaques, the two oxidized lipids may contribute to plaque instability and rupture. They appear to do so by sustaining the release of inflammatory molecules and MMP‐9 by inflammatory and immune cells, for example, macrophages, through activation of TLR4 and its NF‐κB downstream signaling.     

Mast cells in vulnerable coronary plaques: potential mechanisms linking mast cell activation to plaque erosion and rupture

PURPOSE OF REVIEW: A novel link between inflammation and acute coronary syndromes is emerging, in that infiltrating inflammatory cells may convert a clinically silent coronary plaque into a dangerous and potentially lethal plaque. The majority of acute atherothrombotic events now relate to erosion or rupture of such unstable plaques. Here we summarize the molecular mechanisms by which activated mast cells may contribute to plaque erosion or rupture. RECENT FINDINGS: In-vitro experiments have revealed a multitude of paracrine effects exerted by activated mast cells. By secreting heparin proteoglycans and chymase, activated mast cells efficiently inhibit the proliferation of smooth muscle cells in vitro, and reduce their ability to produce collagen by a transforming growth factor beta-dependent and -independent mechanism. Mast cell chymase and tryptase are capable of activating matrix metalloproteinases types 1 and 3, causing degradation of the extracellular matrix component, collagen, necessary for the stability of the plaque. Activated mast cells also secrete matrix metalloproteinases types 1 and 9 themselves. Furthermore, chymase induces SMC apoptosis by degrading fibronectin, a pericellular matrix component necessary for SMC adhesion and survival, with the subsequent disruption of focal adhesions and loss of outside-in survival signaling. By secreting chymase and tumour necrosis factor alpha, activated mast cells also induce endothelial cell apoptosis. SUMMARY: Locally activated mast cells may participate in the weakening of atherosclerotic plaques by secreting heparin proteoglycans, chymase, and cytokines, which affect the growth, function and death of arterial endothelial cells and smooth muscle cells, thereby predisposing to plaque erosion or rupture.     

胆固醇结晶激活动脉粥样硬化斑块巨噬细胞NLRP3炎症体的途径

动脉粥样硬化既是胆固醇在血管壁聚集的疾病,也是发生在动脉壁的一种低强度慢性炎症形式。近年来有研究证实胆固醇结晶在动脉粥样硬化发生发展中具有重要作用。新的显微技术证实,胆固醇结晶在动脉粥样硬化斑块形成的早期即已出现,并与早期炎症有关。胆固醇结晶通过诱发局部炎症,促进大的脂质核心形成;刺破纤维帽,导致斑块破裂进而促进动脉粥样硬化斑块的进展。在影响斑块进程中,NLRP3炎症体的激活对此发挥了重要的作用。NLRP3炎症体是研究最多最明确的炎症体,其与非炎症性疾病的发生发展密切相关。以胆固醇结晶激活NLRP3炎症体的途径作为研究靶点,为动脉粥样硬化的诊断和治疗提供了新的思路和方法。该文就胆固醇结晶在动脉粥样硬化斑块中激活巨噬细胞NLRP3炎症体的两种途径做一综述。     

Detection of the vulnerable coronary atheromatous plaque. Where are we now?

Atherosclerosis is a progressive process with potentially devastating consequences and has been identified as the leading cause of morbidity and mortality, especially in the industrial countries. The underlying mechanisms include endothelial dysfunction, lipid accumulation and enhanced inflammatory involvement resulting in plaque disruption or plaque erosion and subsequent thrombosis. However, it has been made evident, that the majority of rupture prone plaques that produce acute coronary syndromes are not severely stenotic. Conversely, lipid-rich plaques with thin fibrous cap, heavily infiltrated by inflammatory cells have been shown to predispose to rupture and thrombosis, independently of the degree of stenosis. Therefore, given the importance of plaque composition, a continuously growing interest in the development and improvement of diagnostic modalities will promptly and most importantly, accurately detect and characterize the high-risk atheromatous plaque. Use of these techniques may help risk stratification and allow the selection of the most appropriate therapeutic approach.     

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

Atherosclerosis is the main pathophysiological process underlying coronary artery disease (CAD). Acute complications of atherosclerosis, such as myocardial infarction, are caused by the rupture of vulnerable atherosclerotic plaques, which are characterized by thin, highly inflamed, and collagen-poor fibrous caps. Several lines of evidence mechanistically link the heme peroxidase myeloperoxidase (MPO), inflammation as well as acute and chronic manifestations of atherosclerosis. MPO and MPO-derived oxidants have been shown to contribute to the formation of foam cells, endothelial dysfunction and apoptosis, the activation of latent matrix metalloproteinases, and the expression of tissue factor that can promote the development of vulnerable plaque. As such, detection, quantification and imaging of MPO mass and activity have become useful in cardiac risk stratification, both for disease assessment and in the identification of patients at risk of plaque rupture. This review summarizes the current knowledge about the role of MPO in CAD with a focus on its possible roles in plaque rupture and recent advances to quantify and image MPO in plasma and atherosclerotic plaques.     

Biomechanics and Inflammation in Atherosclerotic Plaque Erosion and Plaque Rupture: Implications for Cardiovascular Events in Women

Objective

Although plaque erosion causes approximately 40% of all coronary thrombi and disproportionally affects women more than men, its mechanism is not well understood. The role of tissue mechanics in plaque rupture and regulation of mechanosensitive inflammatory proteins is well established, but their role in plaque erosion is unknown. Given obvious differences in morphology between plaque erosion and rupture, we hypothesized that inflammation in general as well as the association between local mechanical strain and inflammation known to exist in plaque rupture may not occur in plaque erosion. Therefore, our objective was to determine if similar mechanisms underlie plaque rupture and plaque erosion.

Methods and Results

We studied a total of 74 human coronary plaque specimens obtained at autopsy. Using lesion-specific computer modeling of solid mechanics, we calculated the stress and strain distribution for each plaque and determined if there were any relationships with markers of inflammation. Consistent with previous studies, inflammatory markers were positively associated with increasing strain in specimens with rupture and thin-cap fibroatheromas. Conversely, overall staining for inflammatory markers and apoptosis were significantly lower in erosion, and there was no relationship with mechanical strain. Samples with plaque erosion most closely resembled those with the stable phenotype of thick-cap fibroatheromas.

Conclusions

In contrast to classic plaque rupture, plaque erosion was not associated with markers of inflammation and mechanical strain. These data suggest that plaque erosion is a distinct pathophysiological process with a different etiology and therefore raises the possibility that a different therapeutic approach may be required to prevent plaque erosion.     

Platelets: Pleiotropic roles in atherogenesis and atherothrombosis

Platelets are small, anucleate blood elements of critical importance in cardiovascular disease. The ability of platelets to activate and aggregate to form blood clots in response to endothelial injury, such as plaque rupture, is well established. These cells are therefore important contributors to ischaemia in atherothrombosis, and antiplatelet therapy is effective for this reason. However, growing evidence suggests that platelets are also important mediators of inflammation and play a central role in atherogenesis itself. Interactions between activated platelets, leukocytes and endothelial cells trigger autocrine and paracrine activation signals, resulting in leukocyte recruitment at and into the vascular wall. Direct physical interaction may contribute also, through platelet adhesion molecules assisting localization of monocytes to the site of atherogenesis and platelet granule release contributing to the chronic inflammatory milieu which leads to foam cell development and accelerated atherogenesis. Recent studies have shown that antiplatelet therapy in animal models of accelerated atherogenesis can lead to decreased plaque size and improve plaque stability. This review examines the complexity of platelet function and the nature of interactions between activated platelets, leukocytes and endothelial cells. We focus on the growing body of evidence that platelets play a critical role in atherogenesis and contribute to progression of atherosclerosis.     

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.     

Atherosclerosis and oxidative stress

This review focuses on the morphological features of atherosclerosis and the involvement of oxidative stress in the initiation and progression of this disease. There is now consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein in the vascular wall. Reactive oxygen species (ROS) are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis, starting from the initiation of fatty streak development, through lesion progression, to ultimate plaque rupture. Plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction and stroke. Many data support the notion that ROS released from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase (MPO), xanthine oxidase (XO), lipoxygenase (LO), nitric oxide synthase (NOS) and enhanced ROS production from dysfunctional mitochondrial respiratory chain, indeed, have a causatory role in atherosclerosis and other vascular diseases. Moreover, oxidative modifications in the arterial wall can contribute to the arteriosclerosis when the balance between oxidants and antioxidants shifts in favour of the former. Therefore, it is important to consider sources of oxidants in the context of available antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase and transferases thiol-disulfide oxidoreductases and peroxiredoxins. Here, we review also the mechanisms in which they are involved in order to accelerate the pace of the discovery and facilitate development of novel therapeutic approaches.     

Role of plaque inflammation in acute and recurrent coronary syndromes

Inflammation plays an important role in the initiation, development, progression and complications of atherosclerotic vascular disease. Our present knowledge of the elementary role of inflammation for the onset of plaque rupture in atherosclerotic coronary lesions primarily stems from autopsy studies. However, the introduction of directional coronary atherectomy catheters has provided a unique opportunity to directly investigate the role of inflammation in coronary syndromes. In this report we describe the role of coronary plaque inflammation, as determined by immunohistochemistry, on the presentation of coronary syndromes and on the clinical outcome following percutaneous interventions.     

不稳定动脉粥样硬化斑块的研究进展

不稳定斑块破裂及继发血栓形成是导致急性心血管事件发生的主要病理基础。不稳定斑块的形成与炎症反应、细胞凋亡等有密切联系,新近研究表明,组织蛋白酶-S、生长相关基因蛋白-α和内质网应激在动脉粥样硬化斑块趋向不稳定的过程中发挥至关重要的作用。本文就相关研究进展进行综述,为深入了解不稳定斑块的形成机制提供依据。     

Developing a novel rabbit model of atherosclerotic plaque rupture and thrombosis by cold-induced endothelial injury

Background  

It is widely believed that atherosclerotic plaque rupture and subsequent thrombosis leads to acute coronary events and stroke. However, study of the mechanism and treatment of human plaque rupture is hampered by lack of a suitable animal model. Our aim was to develop a novel animal model of atherosclerotic plaque rupture to facilitate the study of human plaque disruption and thrombosis.     

Inflammation in atherosclerosis: a cause or a result of vascular disorders?

Sound data support the concept that in atherosclerosis, inflammation and dyslipidemia intersect each other and that irrespective of the initiator, both participate from the early stages to the ultimate fate of the atheromatous plaque. The two partakers manoeuvre a vicious circle in atheroma formation: dyslipidaemia triggers an inflammatory process and inflammation elicits dyslipidaemia. Independent of the initial cause, the atherosclerotic lesions occur focally, in particular arterial-susceptible sites, by a process that, although continuous, can be arbitrarily divided into a sequence of consecutive stages that lead from fatty streak to the fibro-lipid plaque and ultimately to plaque rupture and thrombosis. In the process, the initial event is a change in endothelial cells (EC) constitutive properties. Then, the molecular alarm signals send by dysfunctional EC are decoded by specific blood immune cells (monocytes, T lymphocytes, neutrophils, mast cells) and by the resident vascular cells, that respond by initiating a robust inflammatory process, in which the cells and the factors they secrete hasten the atheroma development. Direct and indirect crosstalk between the cells housed within the nascent plaque, complemented by the increase in risk factors of atherosclerosis lead to atheroma development and outcome. The initial inflammatory response can be regarded as a defense/protective reaction mechanism, but its further amplification, speeds up atherosclerosis. In this review, we provide an overview on the role of inflammation and dyslipidaemia and their intersection in atherogenesis. The data may add to the foundation of a novel attitude in the diagnosis and treatment of atherosclerosis.     

Doxycycline stabilizes vulnerable plaque via inhibiting matrix metalloproteinases and attenuating inflammation in rabbits

Enhanced matrix metalloproteinases (MMPs) activity is implicated in the process of atherosclerotic plaque instability. We hypothesized that doxycycline, a broad MMPs inhibitor, was as effective as simvastatin in reducing the incidence of plaque disruption. Thirty rabbits underwent aortic balloon injury and were fed a high-fat diet for 20 weeks. At the end of week 8, the rabbits were divided into three groups for 12-week treatment: a doxycycline-treated group that received oral doxycycline at a dose of 10 mg/kg/d, a simvastatin-treated group that received oral simvastatin at a dose of 5 mg/kg/d, and a control group that received no treatment. At the end of week 20, pharmacological triggering was performed to induce plaque rupture. Biochemical, ultrasonographic, pathologic, immunohistochemical and mRNA expression studies were performed. The results showed that oral administration of doxycycline resulted in a significant increase in the thickness of the fibrous cap of the aortic plaque whereas there was a substantial reduction of MMPs expression, local and systemic inflammation, and aortic plaque vulnerability. The incidence of plaque rupture with either treatment (0% for both) was significantly lower than that for controls (56.0%, P<0.05). There was no significant difference between doxycycline-treated group and simvastatin-treated group in any serological, ultrasonographic, pathologic, immunohistochemical and mRNA expression measurement except for the serum lipid levels that were higher with doxycycline than with simvastatin treatment. In conclusion, doxycycline at a common antimicrobial dose stabilizes atherosclerotic lesions via inhibiting matrix metalloproteinases and attenuating inflammation in a rabbit model of vulnerable plaque. These effects were similar to a large dose of simvastatin and independent of serum lipid levels.