Immunomodulation of atherosclerosis with a vaccine

Experimental observations have established that the innate and adaptive immune mechanisms both have roles in the modulation of atherosclerosis. The complex function that the immune system has in the pathophysiology of atherosclerosis is highlighted by the fact that both proatherogenic and atheroprotective effects of immune activation can be demonstrated. An immune response to the protein and lipid components of oxidized LDL cholesterol has been observed in experimental models, and immunization with these antigens has generally reduced atherosclerosis. The findings suggest the tantalizing possibility that an atheroprotective vaccine can be developed. Our laboratories have identified several antigenic epitopes in the human apolipoprotein B100 component of LDL cholesterol. Active immunization with some of these epitopes has reduced atherosclerosis in hyperlipidemic mice. We believe, therefore, that a vaccine based on apolipoprotein B100-related peptide could have a role in reducing atherosclerosis. In this review, we discuss the possible immunologic mechanisms by which vaccines against atherosclerosis might work and the ways in which such treatment might be most effectively administered.     

Angiopoietins,abdominal aortic aneurysm and atherosclerosis

Abdominal aortic aneurysm (AAA) and atherosclerosis are common causes of mortality and morbidity in an aging population. Angiogenesis is believed to contribute to the development and progression of these diseases. Angiopoietins (angpts) are known to be important regulators of angiogenesis. Angpts can also influence inflammation and have been shown to possess both pro-atherosclerotic and atheroprotective effects. This review explores the potential roles that the angpts play in the development and progression of AAA and atherosclerosis.     

Aging and atherosclerosis in human and nonhuman primates

Atherosclerosis is a major age-related process and public health problem and its clinical manifestations (coronary heart disease [CHD] and cerebrovascular disease) continue to be responsible for approximately 50% of all deaths occurring annually. In addition, CHD is responsible for over 70 to 80% of deaths among men and women over 65 years old. As our population ages (35 million people over the age of 65 in the U.S. by the year 2030) and because of the increased morbidity and mortality associated with atherosclerosis, an understanding of the role of aging in the development of atherosclerosis is needed. Multiple risk factors such as smoking, gender, hypertension, and lipids contribute to the development of atherosclerosis. However, these risk factors in combination explain only about half of the individual variability in incidence of CHD, and it has been hypothesized that age-related conditions may play a role. To propectively evaluate the effects of age per se on atherosclerosis progression in humans would require observation over many years. Thus, animal models that are representative of both aging processes and atherosclerosis would be extremely valuable. As such, nonhuman primates have been used extensively in atherosclerosis research. However, studies that will specifically evaluate the role of aging per se in contributing to development of atherosclerosis in nonhuman primates have only recently been initiated. In this review, the contribution of nonhuman primates to atherosclerosis research will be discussed, as will the development of atherosclerosis in both human and nonhuman primates. In addition, a role for age-related conditions in atherosclerosis development in both human and nonhuman primates will be outlined.     

Can menopausal hormone therapy prevent coronary heart disease?

Observational studies show that women who take menopausal hormone therapy (MHT) have a greatly reduced risk of coronary heart disease (CHD). But in some large randomized controlled trials, MHT failed to decrease CHD and so has been deemed inappropriate for long-term prophylaxis against atherosclerosis or other chronic diseases associated with the menopause. Despite the apparent strength of this conclusion, several recent reports suggest that MHT could be atheroprotective when started close to the menopause, and effects of early discontinuation of MHT have never been studied in randomized trials. Here, we examine these reports and highlight existing uncertainty regarding the effects of long-term continuation versus early discontinuation of early-start MHT on atherosclerosis and CHD risk. We call for new research on this question, and an evidence-based review of existing recommendations for MHT.     

The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis

Tissue factor pathway inhibitor (TFPI) is the main inhibitor of tissue factor (TF)-mediated coagulation. In atherosclerotic plaques TFPI co-localizes with TF, where it is believed to play an important role in attenuating TF activity. Findings in animal models such as TFPI knockout models and gene transfer models are consistent on the role of TFPI in arterial thrombosis as they reveal an active role for TFPI in attenuating arterial thrombus formation. In addition, ample experimental evidence exists indicating that TFPI has inhibitory effects on both smooth muscle cell migration and proliferation, both which are recognized as important pathological features in atherosclerosis development. Nonetheless, the clinical relevance of these antithrombotic and atheroprotective effects remains unclear. Paradoxically, the majority of clinical studies find increased instead of decreased TFPI antigen and activity levels in atherothrombotic disease, particularly in atherosclerosis and coronary artery disease (CAD). Increased TFPI levels in cardiovascular disease might result from complex interactions with established cardiovascular risk factors, such as hypercholesterolemia, diabetes and smoking. Moreover, it is postulated that increased TFPI levels reflect either the amount of endothelial perturbation and platelet activation, or a compensatory mechanism for the increased procoagulant state observed in cardiovascular disease. In all, the prognostic value of plasma TFPI in cardiovascular disease remains to be established. The current review focuses on TFPI in clinical studies of asymptomatic and symptomatic atherosclerosis, coronary artery disease and ischemic stroke, and discusses potential atheroprotective actions of TFPI.     

Role of integrins in endothelial mechanosensing of shear stress

The focal pattern of atherosclerotic lesions in arterial vessels suggests that local blood flow patterns are important factors in atherosclerosis. Although disturbed flows in the branches and curved regions are proatherogenic, laminar flows in the straight parts are atheroprotective. Results from in vitro studies on cultured vascular endothelial cells with the use of flow channels suggest that integrins and the associated RhoA small GTPase play important roles in the mechanotransduction mechanism by which shear stress is converted to cascades of molecular signaling to modulate gene expression. By interacting dynamically with extracellular matrix proteins, the mechanosensitive integrins activate RhoA and many signaling molecules in the focal adhesions and cytoplasm. Through such mechanotransduction mechanisms, laminar shear stress upregulates genes involved in antiapoptosis, cell cycle arrest, morphological remodeling, and NO production, thus contributing to the atheroprotective effects. This review summarizes some of the recent findings relevant to these mechanotransduction mechanisms. These studies show that integrins play an important role in mechanosensing in addition to their involvement in cell attachment and migration.     

Immunization for atherosclerosis

This review summarizes experimental findings that highlight the complex roles of the immune system in atherogenesis. Immune activation can have either proatherogenic or atheroprotective effects. Immune-modulation therapy via an active or passive immunization strategy aims to exploit the atheroprotective aspects of the immune system to modulate atherosclerosis. Several experimental studies have demonstrated that such an approach is feasible and effective, raising the tantalizing possibility that an atheroprotective vaccine can be developed for clinical testing. Several potential immunogens have been identified and tested for their atheroprotective efficacy with variable results. Although several questions such as choice of optimal antigens, choice of most effective adjuvants, the optimal route of administration, durability of effects, and safety remain to be answered, we believe that a vaccine-based approach to manage atherosclerotic cardiovascular disease is a potentially viable paradigm.     

Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine

Abstract. Wigren M, Kolbus D, Dunér P, Ljungcrantz I, Söderberg I, Björkbacka H, Fredrikson GN, Nilsson J. (Malmö University Hospital, Lund University; Malmö University, Malmo; Sweden) Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 2011; 269 : 546–556. Objectives. Autoimmune responses against oxidized low‐density lipoprotein are considered to play an important pro‐inflammatory role in atherosclerosis and to promote disease progression. T‐regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self‐tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. Design. Six‐week‐old Apoe^?/? mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. Results. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)‐induced interferon‐γ, interleukin (IL)‐4, and IL‐10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A‐induced splenic T‐cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210‐induced Treg activation as well as the reduction of atherosclerosis. Conclusions. The present findings demonstrate that immunization of Apoe^?/? mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis‐related autoimmunity by antigen‐specific activation of Tregs represents a novel approach for treatment of atherosclerosis.     

Myocardial bridges are free from atherosclerosis: Overview of the underlying mechanisms

Myocardial bridging constitutes a congenital, usually benign, coronary abnormality defined as a segment of a major epicardial coronary artery that follows an intramural course through the myocardium. On the basis of clinical and histopathological data, myocardial bridges appear to be spared from atherosclerosis. Although the mechanisms involved are largely unknown, the surrounding myocardium appears to be a key factor by generating a unique atheroprotective hemodynamic microenvironment within bridges. The main components of this environment include low tensile stress and high shear stress. Reduced coronary wall motion due to external support of the surrounding myocardium may also play a role. Better investigation of these mechanisms in appropriate animal models is anticipated to advance our understanding of the pathophysiology of atherosclerosis, providing a framework for the development of new atheroprotective strategies.     

HDL biogenesis and functions: Role of HDL quality and quantity in atherosclerosis

Coronary heart disease (CHD) is a leading cause of death in western societies. In the last few decades, a number of epidemiological studies have shown that a disproportion between atheroprotective and atherogenic lipoproteins in plasma is one of the most important contributors towards atherosclerosis and CHD. Thus, based on the classical view, reduced HDL cholesterol levels independently predict one's risk factor for developing cardiovascular disease, while elevated HDL levels protect from atherosclerosis. However, more recent studies have suggested that the relationship between HDL and cardiovascular risk is more complex and extends beyond the levels of HDL in plasma. These studies challenge the existing view on HDL and cardiovascular risk and trigger a discussion as to whether low HDL is a causal effect for the development of heart disease. In this article we provide a review of the current literature on the biogenesis of HDL and its proposed functions in atheroprotection. In addition, we discuss the significance of both HDL quality and quantity in assessing cardiovascular risk.     

Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link?

Both osteoporosis and cardiovascular disease (CVD) are major public health problems leading to increased morbidity and mortality. Although traditionally viewed as separate disease entities that increase in prevalence with aging, accumulating evidence indicates that there are similar pathophysiological mechanisms underlying both diseases. In addition to menopause and advanced age, other risk factors for CVD such as dyslipidemia, oxidative stress, inflammation, hyperhomocystinemia, hypertension, and diabetes have also been associated with increased risk of low bone mineral density (LBMD). Elevated LDL and low HDL cholesterol are associated with LBMD, altered lipid metabolism is associated with both bone remodeling and the atherosclerotic process, which might explain, in part, the co-existence of osteoporosis and atherosclerosis in patients with dyslipidemia. Similarly, inflammation plays a pivotal role in both atherosclerosis and osteoporosis. Elevated plasma homocysteine levels are associated with both CVD and osteoporosis. Nitric oxide (NO), in addition to its known atheroprotective effects, appears to also play a role in osteoblast function and bone turnover. Supporting this notion, in a small randomized controlled trial, nitroglycerine (an NO donor) was found to be as effective as estrogen in preventing bone loss in women with surgical menopause. Statins, agents that reduce atherogenesis, also stimulate bone formation. Furthermore, bisphosphonates, used in the treatment of osteoporosis, have been shown to inhibit atherogenesis. Intravenous bisphosphonate therapy significantly decreases serum LDL and increases HDL in postmenopausal women. The exciting possibilities of newer pharmacological agents that effectively treat both osteoporosis and CVD hold considerable promise. However, it is important to emphasize that the current evidence linking both of these diseases is far from conclusive. Therefore, additional research is necessary to further characterize the relationship between these two common illnesses.     

Use of statins for secondary prevention

Opinion statement The causal role of hyperlipidemia in the pathogenesis of atherosclerosis is beyond dispute. The principal lipid abnormality responsible for coronary heart disease (CHD) is considered to be the elevation of the low-density lipoprotein cholesterol (LDL-C), although reduced levels of high-density lipoprotein cholesterol, and most recently elevated triglyceride levels, have also been associated with increased risk for CHD. The risk with these lipid abnormalities exists both in the asymptomatic population as well as in individuals with clinical evidence of atherosclerosis. Most patients with established CHD, and noncoronary atherosclerosis, will need drug therapy to achieve their National Cholesterol Education Program Adult Treatment Panel LDL-C goal of less than 100 mg/dL; the most efficacious, safe, and well-tolerated drugs for this purpose are the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins. The role of statins for secondary cardiovascular disease prevention has been well established in several large randomized clinical trials. New data now suggest that statins offer significant benefits to a broad range of patients at high global CHD risk, and should be regarded as an integral part of the management of acute coronary syndromes.     

Role of regulatory T cells in atheroprotective effects of granulocyte colony-stimulating factor

We and others have previously reported that granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling and dysfunction after myocardial infarction in animal models and human. We have also reported that G-CSF inhibits the progression of atherosclerosis in animal models, but its precise mechanism is still elusive. So, we examined the effects of G-CSF on atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. Twelve-week-old male ApoE(-/-) mice were subcutaneously administrated with 200 μg/kg of G-CSF or saline once a day for 5 consecutive days per a week for 4 weeks. Atherosclerotic lesion of aortic sinus was significantly reduced in the G-CSF-treated mice compared with the saline-treated mice (35% reduction, P<0.05). G-CSF significantly reduced the expression level of interferon-γ by 31% and increased the expression level of interleukin-10 by 20% in atherosclerotic lesions of aortic sinus. G-CSF increased the number of CD4(+)CD25(+) regulatory T cells in lymph nodes and spleen, and enhanced the suppressive function of regulatory T cells in vitro. G-CSF markedly increased the number of Foxp3-positive regulatory T cells in atherosclerotic lesions of aortic sinus. Administration of anti-CD25 antibody (PC61) that depletes regulatory T cells abrogated these atheroprotective effects of G-CSF. Moreover, in ApoE(-/-)/CD28(-/-) mice, that lack regulatory T cells, the protective effects of G-CSF on atherosclerosis were not recognized. These findings suggest that regulatory T cells play an important role in the atheroprotective effects of G-CSF.     

Minireview: estrogen and mouse models of atherosclerosis

The use of hormone replacement therapy for coronary heart disease prevention in humans has been an area of intense controversy. The atheroprotective qualities of estrogens have been challenged recently by several negative results of randomized clinical trials in postmenopausal women. However, the inhibitory effects of estrogens on atherogenesis are well documented in numerous animals, including atherosclerotic mouse models, but the detailed mechanisms of this protection are not understood. In this minireview, we will focus on the considerable success that has been achieved in demonstrating the atheroprotective effects of 17beta-estradiol in apolipoprotein E and low-density lipoprotein receptor-deficient mice and the use of these atherosclerotic mouse models in pharmacological and genetic study designs to investigate antiatherogenic mechanisms of estrogens. Mouse models of atherosclerosis should prove beneficial to understanding the cellular and molecular mechanisms of estrogen-mediated atheroprotection and aid the development of improved therapies to confer the benefits and reduce the risks associated with hormone replacement therapy.     

Narrowing in on cardiovascular disease: the atheroprotective role of peroxisome proliferator-activated receptor gamma

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that has been suggested to play protective roles in the pathogenesis of diseases that are characterized by chronic inflammation, such as atherosclerosis. The study of nuclear receptors, including PPAR gamma, has led to the discovery of anti-inflammatory processes that are collectively known as transrepression. In this review, we will highlight some of the mechanisms of PPAR gamma-mediated transrepression that have surfaced throughout the past decade. We will also discuss the existing evidence for an atheroprotective role of PPAR gamma as a repressor of inflammatory genes and as a key determinant of distinct monocyte-derived subpopulations that may serve an anti-inflammatory, homeostatic role in atherogenesis.     

Experimental Models for the Investigation of High-Density Lipoprotein–Mediated Cholesterol Efflux

Reduction of low-density lipoprotein cholesterol by statin therapy has only modestly decreased coronary heart disease (CHD)-associated mortality in developed countries, which has prompted the search for alternative therapeutic strategies for CHD. Epidemiologic and interventional studies have clearly established an inverse association between plasma levels of high-density lipoprotein (HDL) cholesterol and incidence of atherosclerosis. The atheroprotective benefits of HDL are not only dependent on HDL concentrations (quantity), but also on HDL function (quality). Therefore, several techniques have been recently developed to assess the different properties of HDL. Because reverse cholesterol transport (RCT) is considered a key player in the beneficial action of HDL, this review focuses on the different methods used to evaluate cholesterol efflux. Measuring the in vivo function of HDL could be of significant importance for both the clinical evaluation of an individual patient and to evaluate the effectiveness of different RCT-enhancing therapeutic approaches.     

Nonpharmacologic approaches for the treatment of hyperlipidemia

Coronary heart disease (CHD) is the leading cause of death in the United States. Dyslipidemias, like decreased high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL), have been linked through epidemiologic and experimental studies with the development of atherosclerosis and an increased risk of CHD. The introduction of various classes of lipid-lowering drugs, especially the hydroxymethylglutaryl-coenzyme-A-reductase inhibitors (statins), has allowed for effective treatment of hyperlipidemia. This article reviews the following nonpharmacologic approaches to hyperlipidemia: LDL apheresis, surgery, the emergence of HDL as a therapeutic target, gene therapy, and finally, the possibility of developing a vaccine against atherosclerosis.