Proteomics in atherothrombosis: a future perspective

Atherothrombosis is the primary cause of death in Western countries. The cellular and molecular mechanisms underlying atherosclerosis remain widely unknown. The complex nature of atherosclerotic cardiovascular diseases demands the development of novel technologies that enable discovery of new biomarkers for early disease detection and risk stratification, which may predict clinical outcome. In this review, we outline potential sources and recent proteomic approaches that could be applied in the search of novel biomarkers of cardiovascular risk. In addition, we describe some issues raised in relation to the application of proteomics to blood samples, as well as two novel emerging concepts, such as peptidomics and population proteomics. In the future, the use of high-throughput techniques (proteomic, genomics and metabolomics) will potentially identify novel patterns of biomarkers, which, along with traditional risk factors and imaging techniques, could help to target vulnerable patients and monitor the beneficial effects of pharmacological agents.     

Proteomics in atherothrombosis: a future perspective

Atherothrombosis is the primary cause of death in Western countries. The cellular and molecular mechanisms underlying atherosclerosis remain widely unknown. The complex nature of atherosclerotic cardiovascular diseases demands the development of novel technologies that enable discovery of new biomarkers for early disease detection and risk stratification, which may predict clinical outcome. In this review, we outline potential sources and recent proteomic approaches that could be applied in the search of novel biomarkers of cardiovascular risk. In addition, we describe some issues raised in relation to the application of proteomics to blood samples, as well as two novel emerging concepts, such as peptidomics and population proteomics. In the future, the use of high-throughput techniques (proteomic, genomics and metabolomics) will potentially identify novel patterns of biomarkers, which, along with traditional risk factors and imaging techniques, could help to target vulnerable patients and monitor the beneficial effects of pharmacological agents.     

A historical perspective towards a non-invasive treatment for patients with atherosclerosis

The history of atherosclerosis and cardiovascular disease dates back to ancient times. From the teachings of Galen to the response-to-injury hypothesis of Russel Ross, we have now arrived at the concept of the vulnerable plaque. Next to the development of new treatment options for patients with atherosclerosis, also novel diagnostic imaging techniques have been developed to visualise the arterial wall and to characterise plaque composition. In this article the historical context of atherosclerosis and the attempts towards a noninvasive therapy for patients with atherosclerotic diseases are described. (Neth Heart J 2009;17: 140–5.)     

Cardiovascular co-morbidity in patients with rheumatic diseases

During recent years atherosclerosis, the major cause of cardiovascular disease (CVD), has been recognised as a chronic inflammatory condition in which rupture of atherosclerotic lesions appears to play a major role. The risk of CVD is raised in many rheumatic diseases. This risk is high in systemic lupus erythematosus - as much as a 50-times increase among middle-aged women has been reported. Studies on CVD and atherosclerosis in rheumatic disease could thus provide interesting information about CVD and atherosclerosis in addition to being an important clinical problem. A combination of traditional and nontraditional risk factors accounts for the increased risk of CVD and atherosclerosis in rheumatic disease. One interesting possibility is that atherosclerotic lesions in rheumatic disease are more prone to rupture than normal atherosclerotic lesions. It is also likely that increased risk of thrombosis may play an important role, not least in systemic lupus erythematosus. Further, it is not clear whether an increased risk of CVD is a general feature of rheumatic disease, or whether this only occurs among subgroups of patients. It should be emphasised that there is an apparent lack of treatment studies where CVD in rheumatic disease is the end point. Control of disease activity and of traditional risk factors, however, appears to be well founded in relation to CVD in rheumatic disease. Further studies are needed to determine the exact role of lipid-lowering drugs as statins. Hopefully novel therapies can be developed that target the causes of the inflammation in atherosclerotic lesions both in rheumatic patients and in the general population.     

Effect of phenolic acids of microbial origin on production of reactive oxygen species in mitochondria and neutrophils

Cardiovascular death is frequently associated with atherosclerosis, a chronic multifactorial disease and a leading cause of death worldwide. Genetically engineered mouse models have proven useful for the study of the mechanisms underlying cardiovascular diseases. The apolipoprotein E-deficient mouse has been the most widely used animal model of atherosclerosis because it rapidly develops severe hypercholesterolemia and spontaneous atherosclerotic lesions similar to those observed in humans. In this review, we provide an overview of the cardiac and vascular phenotypes and discuss the interplay among nitric oxide, reactive oxygen species, aging and diet in the impairment of cardiovascular function in this mouse model.     

Cardiac and vascular phenotypes in the apolipoprotein E-deficient mouse

Cardiovascular death is frequently associated with atherosclerosis, a chronic multifactorial disease and a leading cause of death worldwide. Genetically engineered mouse models have proven useful for the study of the mechanisms underlying cardiovascular diseases. The apolipoprotein E-deficient mouse has been the most widely used animal model of atherosclerosis because it rapidly develops severe hypercholesterolemia and spontaneous atherosclerotic lesions similar to those observed in humans. In this review, we provide an overview of the cardiac and vascular phenotypes and discuss the interplay among nitric oxide, reactive oxygen species, aging and diet in the impairment of cardiovascular function in this mouse model.     

Role of AMPK in atherosclerosis via autophagy regulation

Atherosclerosis is characterized by the accumulation of lipids and deposition of fibrous elements in the vascular wall, which is the primary cause of cardiovascular diseases. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor of energy metabolism that regulates multiple physiological processes, including lipid and glucose metabolism and the normalization of energy imbalances. Overwhelming evidence indicates that AMPK activation markedly attenuates atherosclerosis development. Autophagy inhibits cell apoptosis and inflammation and promotes cholesterol efflux and efferocytosis. Physiological autophagy is essential for maintaining normal cardiovascular function. Increasing evidence demonstrates that autophagy occurs in developing atherosclerotic plaques. Emerging evidence indicates that AMPK regulates autophagy via a downstream signaling pathway. The complex relationship between AMPK and autophagy has attracted the attention of many researchers because of this close relationship to atherosclerosis development. This review demonstrates the role of AMPK and autophagy in atherosclerosis. An improved understanding of this interrelationship will create novel preventive and therapeutic strategies for atherosclerosis.     

Lifestyle management to prevent atherosclerotic cardiovascular disease: evidence and challenges

Netherlands Heart Journal - Lifestyle management is the cornerstone of both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) and the importance of lifestyle...     

Smooth muscle-specific HuR knockout induces defective autophagy and atherosclerosis

Human antigen R (HuR) is a widespread RNA-binding protein involved in homeostatic regulation and pathological processes in many diseases. Atherosclerosis is the leading cause of cardiovascular disease and acute cardiovascular events. However, the role of HuR in atherosclerosis remains unknown. In this study, mice with smooth muscle-specific HuR knockout (HuR^SMKO) were generated to investigate the role of HuR in atherosclerosis. HuR expression was reduced in atherosclerotic plaques. As compared with controls, HuR^SMKO mice showed increased plaque burden in the atherosclerotic model. Mechanically, HuR could bind to the mRNAs of adenosine 5′-monophosphate-activated protein kinase (AMPK) α1 and AMPKα2, thus increasing their stability and translation. HuR deficiency reduced p-AMPK and LC3II levels and increased p62 level, thereby resulting in defective autophagy. Finally, pharmacological AMPK activation induced autophagy and suppressed atherosclerosis in HuR^SMKO mice. Our findings suggest that smooth muscle HuR has a protective effect against atherosclerosis by increasing AMPK-mediated autophagy.Subject terms: Cardiovascular diseases, Pathogenesis     

冠状动脉钙化及相关中草药的作用

动脉钙化（AC）,尤其是属于动脉内膜钙化的冠状动脉钙化（CAC）,是动脉粥样硬化过程中的一种病理现象。最初,CAC是减轻动脉粥样硬化炎症的一种自我保护机制。但是,它也是造成动脉粥样硬化斑块破裂的重要原因。尤其是CAC早期的微钙化,这是斑块破裂的主要原因。从早期的微钙化到后期动脉钙化的稳定融合,不同程度的CAC对心血管事件有不同影响。数百年来,中草药（CHM）一直被用于治疗动脉粥样硬化性心血管疾病。CHM如何有效治疗CAC及其病理机制有待进一步研究。本文回顾了CAC发生的分子机制以及CHM对这些病理过程的影响。     

Cardiovascular risk in pediatric-onset rheumatological diseases

Cardiovascular morbidity and mortality are becoming major health concerns for adults with inflammatory rheumatic diseases. The enhanced atherogenesis in this patient population is promoted by the exposure to traditional risk factors as well as nontraditional cardiovascular insults, such as corticosteroid therapy, chronic inflammation and autoantibodies. Despite definite differences between many adult-onset and pediatric-onset rheumatologic diseases, it is extremely likely that atherosclerosis will become the leading cause of morbidity and mortality in this pediatric patient population. Because cardiovascular events are rare at this young age, surrogate measures of atherosclerosis must be used. The three major noninvasive vascular measures of early atherosclerosis - namely, flow-mediated dilatation, carotid intima-media thickness and pulse wave velocity - can be performed easily on children. Few studies have explored the prevalence of cardiovascular risk factors and even fewer have used the surrogate vascular measures to document signs of early atherosclerosis in children with pediatric-onset rheumatic diseases. The objective of this review is to provide an overview on cardiovascular risk and early atherosclerosis in pediatric-onset systemic lupus erythematosus, juvenile idiopathic arthritis and juvenile dermatomyositis patients, and to review cardiovascular preventive strategies that should be considered in this population.     

Genetic determinants of platelet function in thromboembolic diseases

Within the past decade our understanding of thromboembolic disorders has become even more sophisticated as recent discoveries have suggested the influence of gene variants on the development of atherosclerotic disease and arterial thrombosis. Candidate genes encode proteins involved in processes relevant to atherosclerosis, ranging from cholesterol metabolism to arterial thrombosis. Platelets are key elements in primary hemostasis, but also in arterial thrombosis. Moreover, a number of genetic polymorphisms of platelet proteins may also induce gain or loss of function, supporting a role predisposing some individuals to thrombotic events. However, after thousands of studies, much controversy remains whether individual platelet polymorphisms contribute to an increased likelihood of thromboembolic disorders. Although platelet polymorphisms are a promising addition to more established cardiovascular risk factors, identifying genetic variants as a single cause of cardiovascular disease would be an oversimplification; instead, the contribution of these polymorphisms should also be considered in the context of a multifactorial disease. Gene-gene and gene-environment studies would identify specific combinations associated with a high risk to suffer from these diseases. The platelet's genetic heterogeneity should also be considered in every aspect of clinical medicine, ranging from susceptibility to diseases, pathogenesis, and clinical outcome to diversity in responses to drug treatment (pharmacogenomics), and bleeding.     

Does a causal relation between cardiovascular disease and periodontitis exist?

Inflammation is believed to play a central part in the pathogenesis of atherosclerosis, and much attention has been paid to the possible association between atherosclerosis and other inflammatory diseases. Periodontal disease is a common inflammatory disease affecting up to 50% of the adult population, and during the past two decades much research has focused on a possible association between periodontitis and cardiovascular disease. Here, we review the existing literature on the association between the two diseases.     

Imagerie moléculaire de la plaque d’athérome vulnérable. Évaluation préclinique et clinique de traceurs radioactifs

Atherosclerotic cardiovascular diseases (CVD) are the leading cause of mortality worldwide, accounting for greater than 19.10⁶ deaths annually. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. Indeed, an acute heart attack is the first symptom of atherosclerosis in as much as 50% of individuals with severe disease. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerosis in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could potentially allow the identification of vulnerable patients by non-invasive scintigraphic imaging following administration of a radiolabeled tracer. The development of radiolabeled probes that specifically bind to and allow the in vivo imaging of vulnerable atherosclerotic plaques is therefore the subject of intense ongoing experimental and clinical research. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET imaging. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable atherosclerotic plaques in the carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of the coronary arteries remains a challenging issue because of the small size of atherosclerotic lesions and of their vicinity with blood and the circulating tracer activity.     

巨细胞病毒参与动脉粥样硬化致病机制研究新进展

人巨细胞病毒(human cytomegalovirus, HCMV)是β疱疹病毒家族成员,在人群中感染率极高,全球成人中血清阳性率可达40%～100%。研究表明,HCMV感染患者更易患心脑血管疾病。动脉粥样硬化(atherosclerosis,AS)是心血管系统疾病中危害健康的一种常见病。大量流行病学研究证明,在AS组织中可检测出较高的HCMV DNA和抗原、抗体,同时回顾性研究发现AS患者多有HCMV暴露因素,提示HCMV可能参与AS致病。本文就HCMV致AS的依据和机制进行综述, 为研究HCMV在AS病理过程中的作用提供全新视角。     

A Murine Model of Obesity With Accelerated Atherosclerosis

The epidemic of obesity sweeping developed nations is accompanied by an increase in atherosclerotic cardiovascular diseases. Dyslipidemia, diabetes, hypertension, and obesity are risk factors for cardiovascular disease. However, delineating the mechanism of obesity‐accelerated atherosclerosis has been hampered by a paucity of animal models. Similar to humans, apolipoprotein E–deficient (apoE^?/?) mice spontaneously develop atherosclerosis over their lifetime. To determine whether apoE^?/? mice would develop obesity with accelerated atherosclerosis, we fed mice diets containing 10 (low fat (LF)) or 60 (high fat (HF)) kcal % from fat for 17 weeks. Mice fed the HF diet had a marked increase in body weight and atherosclerotic lesion formation compared to mice fed the LF diet. There were no significant differences between groups in serum total cholesterol, triglycerides, or leptin concentrations. Plasma concentrations of the acute‐phase reactant serum amyloid A (SAA) are elevated in both obesity and cardiovascular disease. Accordingly, plasma SAA concentrations were increased fourfold (P < 0.01) in mice fed the HF diet. SAA was associated with both pro‐ and antiatherogenic lipoproteins in mice fed the HF diet compared to those fed the LF diet, in which SAA was primarily associated with the antiatherogenic lipoprotein high‐density lipoprotein (HDL). Moreover, SAA was localized with apoB‐containing lipoproteins and biglycan in the vascular wall. Taken together, these data suggest male apoE‐deficient mice are a model of metabolic syndrome and that chronic low level inflammation associated with increased SAA concentrations may mediate atherosclerotic lesion formation.     

Insulin-like growth factor II and its receptors in atherosclerosis and in conditions predisposing to atherosclerosis

PURPOSE OF REVIEW: Growth factors regulate cellular migration, proliferation, and the production of extracellular matrix during the development of the atherosclerotic lesion. Here we discuss experimental evidence pointing to insulin-like growth factor II and its receptors as important players in cardiovascular diseases. RECENT FINDINGS: Genetically modified mice with altered levels of insulin-like growth factor II or receptors mediating insulin-like growth factor II signalling showed abnormalities known to be associated with, or contribute to, ageing and atherosclerosis in humans. These animal models displayed abnormalities in the morphology of the aortic tissue, glucose tolerance, response to oxidative stress and life span. Furthermore, human population studies showed a significant association between polymorphisms in the insulin-like growth factor II gene and obesity, a major risk factor for atherosclerosis. SUMMARY: Direct and indirect evidence in animal models points to insulin-like growth factor II and its signalling receptors as crucial players in atherosclerosis and in the onset of conditions predisposing to the disease. Furthermore, human population studies have established significant associations between specific polymorphisms at the insulin-like growth factor II gene and obesity which is an important risk factor for atherosclerosis. Future investigations should aim at understanding the molecular mechanisms underlying these effects and elucidating the potential role of the type 2 insulin-like growth factor receptor in the development of atherosclerotic lesions.     

Vascular smooth muscle cell proliferation in the pathogenesis of atherosclerotic cardiovascular diseases

Atherosclerosis is the principal cause of myocardial infarction, stroke, and peripheral vascular disease, accounting for nearly half of all mortality in developed countries. For example, it has been estimated that atherosclerosis leads to approximately 500,000 deaths from coronary artery disease and 150,000 deaths from stroke every year in the United States (American Heart Association, 1996). Percutaneous transluminal angioplasty has become a well-established technique for revascularization of occluded arteries. However, the long-term efficacy of the procedure remains limited by progressive vessel renarrowing (restenosis) within the following few months after angioplasty. Abnormal vascular smooth muscle cell (VSMC) proliferation is thought to play an important role in the pathogenesis of both atherosclerosis and restenosis. Accordingly, considerable effort has been devoted to elucidate the mechanisms that regulate cell cycle progression in VSMCs. In the present article, we will review the different factors that are involved in the control of VSMC proliferation, especially in the context of cardiovascular disease. Ultimately, a thorough understanding of these regulatory networks may lead to the development of novel drug and gene therapies for the treatment of cardiovascular diseases. Therapeutic approaches that targeted specific cell-cycle control genes or growth regulatory molecules which effectively inhibited neointimal lesion formation will be also discussed.     

Role of thrombin in the pathogenesis of atherosclerosis

Atherosclerosis is an arterial disease associated with inflammation. Thrombin is a procoagulant and proinflammatory serine protease that contributes to the pathology of atherosclerosis by enhancing the expression of cell adhesion molecules, inducing the secretion of proinflammatory cytokines, activating inflammatory responses in atherosclerotic plaques, stimulating proliferation of aortic smooth muscle cells, and exacerbating vascular lesions at sites of injury. Hence, thrombin appears to be an important target for treatment of atherosclerosis and thrombin pharmacological inhibitors have significant therapeutic potency for suppressing inflammatory responses in cardiovascular diseases. This review summarizes the proinflammatory signaling functions of thrombin as well as the therapeutic potency of thrombin inhibitors in the pathogenesis of atherosclerosis and hence their potential therapeutic value in this condition.