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.     

Cardiovascular autonomic imbalance and baroreflex dysfunction in the apolipoprotein E-deficient mouse

Genetically engineered mouse models and advances in molecular biotechnology have given extensive aid to experimental studies of cardiovascular mechanisms and dysfunction in pathological states such as atherosclerosis. Among the available animal models that have been developed to study atherosclerosis, the apolipoprotein E-deficient (apoE(-/-)) mouse is the most ideal genetically modified animal presently available. The apoE(-/-)mouse develops spontaneous severe hypercholesterolemia in a short-time and subsequently develops atherosclerotic lesions similar to those found in humans. Since its creation two decades ago, the apoE(-/-)mouse has greatly contributed to the understanding of atherosclerosis, but the consequences of hypercholesterolemia and atherosclerosis for the autonomic control of cardiovascular function in this mouse model have not been reviewed. In this article, we provide an overview of abnormalities of the parasympathetic and sympathetic nervous systems controlling heart rate and blood pressure and emphasize the dysfunction of the baroreflex control of cardiovascular function and how this dysfunction is influenced by nitric oxide, reactive oxygen species, aging and an atherogenic diet in the apoE(-/-)mouse.     

Hippo信号通路与心血管发育及疾病调控

心血管疾病已成为中国乃至全球首位死亡原因,探索心血管系统发育及调控异常的原因及相关机制可以为心血管疾病的预防和治疗提供重要的科学依据。Hippo信号通路是新近发现的在调节器官大小、细胞增殖及凋亡、干细胞命运等方面具有重要功能的一条信号通路。Hippo信号通路的不同成分参与心脏血管的发育和心血管细胞增殖、分化等功能调控,影响损伤后修复及再生等过程,该通路调节异常可引起心血管疾病,如心梗、心肌肥大、血管内膜增生、动脉硬化等。本文综述了Hippo信号通路对心血管系统发育和疾病调控的相关研究及最新进展,以期为Hippo通路在心血管疾病的发病机制及临床转化研究提供潜在的理论基础。     

Invited review: Identifying new mouse models of cardiovascular disease: a review of high-throughput screens of mutagenized and inbred strains.

The mouse is a proven model for studying human disease. Many strains exist that exhibit either natural or engineered genetic variation and thereby enable the elucidation of pathways involved in the development of cardiovascular disease. Although those mouse models have been fundamental to advancing our knowledge base, we are still at an early stage in understanding how genes contribute to complex disorders. There remains a need for new animal models that closely represent human disease. To expedite their development, we have established the Center for New Mouse Models of Heart, Lung, Blood, and Sleep Disorders at The Jackson Laboratory. We are using a phenotype-driven approach to identify mutations leading to atherosclerosis, hypertension, obesity, blood disorders, lung dysfunction, thrombosis, and disordered sleep. Our high-throughput, comprehensive phenotyping draws from two sources for new models: 1) the natural variation among over 40 inbred mouse strains and 2) chemically induced, whole-genome mutagenized mice. Here, we review our cardiovascular screens and present some hypertensive, obese, and cardiovascular models identified with this approach.     

Sizing up stability: combination therapy with Apo-AI peptide mimetics and statins in systemic lupus erythematosus-mediated atherosclerosis

In a study published recently in Arthritis Research & Therapy, Woo and colleagues investigated the effects of pravastatin in combination with an apolipoprotein-AI (Apo-AI) mimetic peptide in a mouse model of lupus-accelerated atherosclerosis. Combination treatment resulted in a significant decrease in systemic inflammation but increased aortic root lesion size. However, this treatment changed the phenotype of the lesion to a more stable plaque. Because plaque stability is also important for protection against the deadly manifestations of atherosclerosis, combination therapies using Apo-AI mimetics and statin might offer a good additional therapy to treat autoimmunity and cardiovascular disease in patients with lupus.     

Inhibition of nuclear factor-kappaB attenuates artherosclerosis in apoE/LDLR - double knockout mice.

Nuclear factor - kappaB (NF-kappaB) is a good therapeutic target for cardiovascular disease and numerous efforts are being made to develop safe NF-kappaB inhibitors. Nowadays many authors address NF-kappaB as a major therapeutic target in atherosclerosis, especially for preventive measures, in the light of two main hypothesis of atherosclerosis: oxidation and inflammation. We hypothesized that ammonium pyrrolidinedithioocarbamate (PDTC) - a well-known inhibitor of NF-kappaB could inhibit the development of atherosclerosis in this experimental model. We used apoE/LDLR - DKO mouse model, which is considered as a one of the best models to study the anti-atherosclerotic effect of drugs. In this model PDTC inhibited atherogenesis, measured both by "en face" method (25,15+/-2,9% vs. 15,63+/-0,6%) and "cross-section" method (565867+/-39764 microm2 vs. 291695+/-30384 microm2). Moreover, PDTC did not change the profile of cholesterol and triglycerides in blood. To our knowledge, this is the first report that shows the effect of PDTC on atherogenesis in gene-targeted apoE/LDLR - double knockout mice.     

The role of cytokines in the development of atherosclerosis

Atherosclerosis contributes to the development of many cardiovascular diseases, which remain the leading cause of death in developed countries. Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. It is caused by dyslipidemia and mediated by both innate and adaptive immune responses. Inflammation is a key factor at all stages of atherosclerosis progression. Cells involved in pathogenesis of atherosclerosis were shown to be activated by soluble factors, cytokines, that strongly influence the disease development. Pro-inflammatory cytokines accelerate atherosclerosis progression, while anti-inflammatory cytokines ameliorate the disease. In this review, we discuss the latest findings on the role of cytokines in the development and progression of atherosclerosis.     

Construction and phenotypic analysis of mice carrying a duplication of the major histocompatibility class I (MHC-I) locus

Copy number variation (CNV) has been associated increasingly with altered susceptibility to human disease. Large CNVs are likely to incur disease risk or resilience via predictable changes in gene dosage that are relatively straightforward to model using chromosomal engineering in mice. The classical class I major histocompatibility locus (MHC-I) contains a dense set of genes essential for innate immune system function in vertebrates. MHC-I genes are highly polymorphic and genetic variation in the region is associated with altered susceptibility to a wide variety of common diseases. Here we investigated the role of gene dosage within MHC-I on susceptibility to disease by engineering a mouse line carrying a 1.9-Mb duplication of this region [called Dp(MHC-I)]. Extensive phenotypic analysis of heterozygous (3N) Dp(MHC-I) animals did not reveal altered blood and stem cell parameters, susceptibility to high-fat diet, death by cancer, or contact dermatitis. However, several measures of disease severity in a model of atherosclerosis were improved, suggesting dosage-sensitive modulators of cardiovascular disease. Homozygous Dp(MHC-I)/Dp(MHC-I) mice demonstrated embryonic lethality. These mice serve as a model for studying the consequences of targeted gene dosage alteration in MHC-I with functional and evolutionary implications.     

Molecular biology and gene transfer in atherosclerosis in the stenting era

Atherosclerosis is the major cause of death in the developed world. Understanding the pathogenesis of atherosclerosis has been a major challenge to cardiovascular research over the past several decades. During this period a number of advances in various scientific disciplines has increased our understanding of this disease. These include improved understanding of the structural and functional components of normal vessel wall and more recently the use of cell biology and molecular biology techniques to elucidate the pathogenesis of atherosclerosis. None of these advances has been more dramatic nor has potentially more far reaching consequences as the application of molecular biology and gene technology to the practice of cardiovascular medicine. These developments have already opened new and exciting areas of vascular research and may in the future provide for earlier identification of genetic predisposition to atherosclerosis, strategic planning of preventive therapy and more tailored pharmacologic approaches for established disease.     

A Model of Cardiovascular Disease Giving a Plausible Mechanism for the Effect of Fractionated Low-Dose Ionizing Radiation Exposure

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally exposed groups receiving small daily radiation doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and cancer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapolation would be appropriate for this endpoint.     

Poloxamer 407-induced atherosclerosis in mice appears to be due to lipid derangements and not due to its direct effects on endothelial cells and macrophages

Coronary heart disease secondary to atherosclerosis is still the leading cause of death in the US. Animal models used for elucidating the pathogenesis of this disease primarily involve rabbits and pigs. Previous studies from this laboratory have demonstrated intraperitoneal injections of poloxamer 407 (P-407) in both male and female mice will lead to hyperlipidemia and atherosclerosis, suggesting the use of this polymer to develop a mouse model of atherosclerosis. In order to understand the mechanism of P-407-induced hyperlipidemia and vascular lesion formation, we evaluated the direct effects of P-407 on endothelial cell and macrophage functions in vitro, and its in vivo effects on the oxidation of circulating lipids following long-term (4 month) administration. Our results demonstrated that incubation of P-407 with human umbilical vein endothelial cells in culture did not influence either cell proliferation or interleukin-6 and interleukin-8 production over a concentration range of 0-40 microM. In addition, nitric oxide production by macrophages was not affected by P-407 over a concentration range of 0-20 microM. Finally, we demonstrated that while P-407 could not induce the oxidation of LDL-C in vitro, long-term (4 month) administration of P-407 in mice resulted in elevated levels of oxidized lipids in the plasma. Thus, it is suggested that the formation of atherosclerotic lesions in this mouse model of atherosclerosis does not result from either direct stimulation of endothelial cells or macrophage activation by P-407. Instead, these data would support the premise that oxidation of lipids (perhaps low-density lipoprotein cholesterol) by an indirect mechanism following injection of P-407 may represent one of the mechanisms responsible for atheroma formation.     

The role of proteomics in clinical cardiovascular biomarker discovery

Cardiovascular disease remains the most common cause of death in the developed world and is predicted by the World Health Organization to kill approximately 20 million people worldwide each year until at least 2015. In light of these figures, work on producing superior tools for clinical use in the cardiovascular field is intensive. As proteins are the primary effectors of cellular function, a significant majority of this work focuses on the role of proteins in the cardiovascular system in physiological and pathological states in order to outline both mechanisms and markers of disease. One of the most effective ways to investigate these on a global basis is through proteomic analysis, which allows for broad spectrum screening of cellular protein or peptide complements during cardiovascular pathogenesis. Furthermore, specific technologies are now available to screen animal model or human blood samples for novel, improved markers of chronic disease states, such as atherosclerosis or for earlier indicators of acute myocardial stress, including ischemia/reperfusion injury and heart failure. This review summarizes current literature on the key aspects of proteomics and peptidomics related to clinical cardiovascular science.     

Autophagy as mechanism for cell death in degenerative aortic valve disease

Once degenerative aortic valve disease becomes symptomatic, valve replacement is necessary for prognostic and symptomatic reasons. In elderly patients, symptoms of degenerative aortic valve can often be doubtful. Therefore, it is difficult but important to distinguish patients who need surgery from those who do not. Estimation of the rate of the progression of this disease can be helpful herein because one needs to bear in mind that aortic valve degeneration is an active process, which can influence the rate of progression. Recently, autophagy was discovered as a mechanism of cell death in different cardiovascular diseases such as atherosclerosis, aortic valve degeneration, heart failure and at regions around heart infarctions. Thus understanding autophagy in all its details can be helpful to contribute insights into the cell death machinery of cardiovascular diseases. This could open ways for inhibition of cell death in cardiovascular disease and possibly define targets for future drug design.     

The Yin and Yang of carbon nanomaterials in atherosclerosis

With unique characteristics such as high surface area, capacity of various functionalization, low weight, high conductivity, thermal and chemical stability, and free radical scavenging, carbon nanomaterials (CNMs) such as carbon nanotubes (CNTs), fullerene, graphene (oxide), carbon nanohorns (CNHs), and their derivatives have increasingly been utilized in nanomedicine and biomedicine. On the one hand, owing to ever-increasing applications of CNMs in technological and industrial fields as well as presence of combustion-derived CNMs in the ambient air, the skepticism has risen over the adverse effects of CNMs on human being. The influences of CNMs on cardiovascular system and cardiovascular diseases (CVDs) such as atherosclerosis, of which consequences are ischemic heart disease and ischemic stroke, as the main causes of death, is of paramount importance. In this regard, several studies have been devoted to specify the biomedical applications and cardiovascular toxicity of CNMs. Therefore, the aim of this review is to specify the roles and applications of various CNMs in atherosclerosis, and also identify the key role playing parameters in cardiovascular toxicity of CNMs so as to be a clue for prospective deployment of CNMs.     

动脉粥样硬化脂代谢紊乱与DNA甲基化的关系

心血管疾病是导致人类死亡的主要原因之一,动脉粥样硬化(Atherosclerosis,As)是心血管疾病的重要病理基础,炎症反应是动脉粥样硬化的重要病理机制。脂代谢紊乱是动脉粥样硬化的独立危险因素,贯穿动脉粥样硬化的始终,并且是导致炎症反应发生的重要原因。DNA甲基化是一种不改变基因核苷酸序列而能调控基因表达的一种重要的表观遗传学方式。有研究证明,脂代谢紊乱的发生、发展与DNA甲基化存在密切关系。本文将围绕与脂代谢紊乱相关基因对动脉粥样硬化过程中脂代谢紊乱与DNA甲基化的关系做一综述。     

A new mouse mutant for the LDL receptor identified using ENU mutagenesis

In an effort to discover new mouse models of cardiovascular disease using N-ethyl-N-nitrosourea (ENU) mutagenesis followed by high-throughput phenotyping, we have identified a new mouse mutation, C699Y, in the LDL receptor (Ldlr), named wicked high cholesterol (WHC). When WHC was compared with the widely used Ldlr knockout (KO) mouse, notable phenotypic differences between strains were observed, such as accelerated atherosclerotic lesion formation and reduced hepatosteatosis in the ENU mutant after a short exposure to an atherogenic diet. This loss-of-function mouse model carries a single base mutation in the Ldlr gene on an otherwise pure C57BL/6J (B6) genetic background, making it a useful new tool for understanding the pathophysiology of atherosclerosis and for evaluating additional genetic modifiers regulating hyperlipidemia and atherogenesis. Further investigation of genomic differences between the ENU mutant and KO strains may reveal previously unappreciated sequence functionality.     

N-3 vs. saturated fatty acids: Effects on the arterial wall

Cardiovascular disease is a leading cause of death worldwide. Atherosclerosis and unstable plaques are underlying causes for cardiovascular diseases. Cardiovascular disease is associated with consumption of diets high in saturated fats. In contrast there is increasing evidence that higher intakes of dietary n-3 fatty acids decrease risk for cardiovascular disease. Recent studies are beginning to clarify how n-3 compared with saturated fatty acids influence cardiovascular disease risk via pathways in the arterial wall. In this paper we will review studies that report on mechanisms whereby dietary fatty acids affect atherosclerosis through modulation of arterial wall lipid deposition, inflammation, cell proliferation, and plaque vulnerability.