Current Pharmaceutical Design - Volume 21, Issue 9, 2015

Innate and adaptive immunity has been shown to be critically involved in the pathogenesis of atherosclerosis. In particular, immune suppression mediated by regulatory T cells (Tregs) or tolerogenic dendritic cells (DCs) serves as a vital mechanism for regulating pathogenic chronic inflammation in atherogensis, suggesting that promotion of endogenous regulatory immune responses could be a possible therapeutic approach to suppress atherosclerotic disease. In this review, we discuss the possible role of Tregs and tolerogenic DCs in the prevention of atherosclerosis and the promising strategies to prevent or cure atherosclerotic disease by modulating regulatory immune responses mediated by these suppressor cells.

Functional heterogeneity of dendritic cells (DCs) observed in atherosclerosis suggest for their complex and multifaced role in the pathogenesis of atherosclerotic disease. A delicate balance between anti-inflammatory and pro-inflammatory mechanisms drives atherogenesis, and local microenvironment triggers the actual involvement of DCs in atherosclerosis-associated inflammation. Responding to microenvironment stimuli, DCs contribute to atherogenesis in both ways being involved in supporting proatherogenic vascular inflammation and by suppressing inflammatory responses via induction of self-tolerogenic properties and regulatory T cells (Tregs). The local microenvironment and extrinsic stimuli influence DC phenotype and hence could control the phenotypic switch toward inflammation or tolerance.

The ability of a human artery to pass through 150 million liters of blood sustaining 2 billion pulsations of blood pressure with minor deterioration depends on unique construction of the arterial wall. Viscoelastic properties of this construction enable to re-seal the occuring damages apparently without direct immediate participance of the constituent cells. Collagen structures are considered to be the elements that determine the mechanoelastic properties of the wall in parallel with elastin responsible for elasticity and resilience. Collagen scaffold architecture is the function-dependent dynamic arrangement of a dozen different collagen types composing three distinct interacting forms inside the extracellular matrix of the wall. Tightly packed molecules of collagen types I, III, V provide high tensile strength along collagen fibrils but toughness of the collagen scaffold as a whole depends on molecular bonds between distinct fibrils. Apart of other macromolecules in the extracellular matrix (ECM), collagen-specific interlinks involve microfilaments of collagen type VI, meshwork-organized collagen type VIII, and FACIT collagen type XIV. Basement membrane collagen types IV, XV, XVIII and cell-associated collagen XIII enable transmission of mechanical signals between cells and whole artery matrix. Collagen scaffold undergoes continuous remodeling by decomposition promoted with MMPs and reconstitution from newly produced collagen molecules. Pulsatile stress-strain load modulates both collagen synthesis and MMP-dependent collagen degradation. In this way the ECM structure becomes adoptive to mechanical challenges. The mechanoelastic properties of the arterial wall are changed in atherosclerosis concomitantly with collagen turnover both type-specific and dependent on the structure. Improving the feedback could be another approach to restore sufficient blood circulation.

The volume of publications on the role of reactive oxygen species (ROS) in biological processes has been increasing exponentially over the last decades. ROS in large amounts clearly have detrimental effects on cell physiology, whereas low concentrations of ROS are permanently produced in cells and play a role as signaling molecules. An imbalance in ROS production and defense mechanisms can lead to pathological vascular remodeling, atherosclerosis being among them. The aim of this review is to examine different sources of ROS from the point of view of their participation in pathogenesis of atherosclerosis and related cardiovascular risk. Among the possible sources of ROS discussed here are mitochondria, NADPH-oxidases, xanthine oxidase, peroxidases, NO-synthases, cytochrome P450, cyclooxygenases, lipoxygenases, and hemoglobin of red blood cells. A great challenge for future research is to establish interrelations, feedback and feed-forward regulation mechanisms of various sources of ROS in development of atherosclerosis and other vascular pathologies.

Atherosclerosis has been widely recognized as a slow progressing inflammatory disease of the aorta and other large caliber arterial vessels. Accumulating evidence suggest that interleukin (IL)-35 can represent an attractive target for future anti-atherosclerotic therapy due to several atheroprotective properties. First, immunosuppressive and anti-inflammatory activity of this cytokine could be beneficial against vascular inflammation. Second, IL-35 can suppress a variety of T cells including proinflammatory Th1 and Th17 cells and probably dendritic cells. Third, IL-35 supports proliferation of regulatory T cells (Tregs), increases their inhibitory function, and induces a new set of Tregs called inducible IL-35-producing Tregs (iTr35 cells). Fourth, this cytokine promotes production of antiinflammatory cytokines such as IL-10 and down-regulates expression of proinflammatory cytokines such as IL-17. Finally, IL-35 is inducible. The fact that IL-35 could be induced by simple compounds such as chemical chaperons may provide advances in developing new efficient strategies for treatment of atherosclerosis. However, it is necessary to test IL-35-inducing factors in order to understand mechanisms of induction and then select the most optimal one. Probably, constructing of humanized antibodies that mimic IL-35 function may provide benefits for advanced atheroprotective therapy.

Tissue factor (TF) is known to be the key element in the initiation of the extrinsic pathway of the coagulation cascade and appears to be a critical determinant of atherosclerotic plaque thrombogenicity. TF is needed to produce thrombin from prothrombin. In the extrinsic pathway, TF activates factor Vll. TF is expressed mainly on subendothelial tissues, but TF expression may be induced on endothelial cells by inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha). Subendothelial TF is responsible for initiating fibrin formation at sites of vascular injury, bloodborne TF may be an important contributor to propagation of the developing thrombus. It has been postulated that the blood-borne TF initiates the thrombogenic stimulus, leading to the formation of larger and more stable thrombus. TF may attach to cellular receptors, which in turn affect the production and release of inflammatory mediators. Baseline plasma TF activity has been demonstrated as an independent predictor for cardiovascular death in patients with acute myocardial infarction. TF is expressed by macrophage-derived foam cells in atherosclerotic plaques. TF levels were higher in atheroma from patients with unstable angina than with stable angina. These results suggest that high levels of TF exposed upon plaque rupture trigger atherothrombosis. Inhibition of TF would be expected to reduce thrombosis associated with a variety of diseases. TF pathway is a potential target for new therapeutic agents that can decrease TF activity, such as active site-inactivated factor VIIa, recombinant TF inhibitor and antibodies against TF or peptides interfering with TF-FVIIa complex activity. Significant clinical forms of atherosclerosis, such as sudden death, myocardial infarction, and stroke have common pathogenesis. The occlusion of the vessel lumen is the result from atherosclerotic plaque rupture/erosion that initiate thrombus formation. This thrombus has complex structure and contains predominantly fibrin in addition to platelets, suggesting an important role for the coagulation cascade in plaque thrombus formation. Tissue factor (TF) is known to be the key element in the initiation of the extrinsic pathway of the coagulation cascade and appears to be a critical determinant of atherosclerotic plaque thrombogenicity.

Atherosclerosis, the primary cause of cardiovascular disease, is a complex and multifactorial pathology resulted from the harmful interactions between genetic and environmental factors. There is a growing body of evidence in support of the role of mitochondrial factors in the pathogenesis of atherosclerosis. Impaired mitochondrial function and structural and qualitative changes in mitochondrial components such as mitochondrial DNA (mtDNA) damage may be directly involved in the development of multiple mechanisms of atherogenesis. Recent findings show that several heteroplasmic mutations of mtDNA are related to atherosclerosis, coronary heart disease and several atherosclerosis-related diseases such as arterial hypertension and diabetes mellitus. Therefore, heteroplasmic mtDNA mutations could represent a promising molecular biomarker of genetic susceptibility to atherosclerosis and related pathologies. This review is focused on the latest findings in the studies of mutations of mitochondrial genome, which are associated with atherosclerosis and atherosclerosis- related diseases.

Interventions aimed to prevent cardiovascular diseases (CVD) are more effective if administered to subjects carefully selected according to their CVD risk. Usually, this risk is evaluated on the basis of the presence and severity of conventional vascular risk factors (VRFs); however, atherosclerosis, the main pathologic substrate of CVD, is not directly revealed by VRFs. The measurement of the arterial wall, using imaging techniques, has increased the early identification of individuals prone to develop atherosclerosis and to quantify its changes over time. B-mode ultrasound is a technique which allows a non-invasive assessment of the arterial wall of peripheral arteries (e.g. extracranial carotid arteries), and provides measures of the intima-media thickness complex (C-IMT) and additional data on the occurrence, localization and morphology of plaques. Being an independent predictor of vascular events, C-IMT has been considered as a tool to optimize the estimation of CVD risk but this application is still a matter of debate. Though the technique is innocuous, relatively inexpensive and repeatable, its use in the clinical practice is limited by the lack of standardized protocols and clear guidelines. This review outlines the rationale for the potential use of C-IMT in the stratification of cardio- and cerebro-vascular risk and discusses several topics related to the measurement of this variable, which are still controversial among experts of the field.

Immunopathology plays important roles in the development of different life-threatening diseases, such as atherosclerosis and its consequences (acute myocardial infarction and stroke), cancer, chronic inflammatory diseases. Effective modulation of the immune system may significantly increase the efficacy of prevention and therapy efforts. Currently there are no marketed drugs capable of normalizing immune system function in an intrinsic and comprehensive way. Here, we describe a test system designed for complex analysis of monocyte activity in individuals to diagnose immunopathology and monitor treatment efficacy. This cell-based test system may also be useful for screening compounds with an immune-correcting effects. Both diagnostic and screening systems are based on primary culture of human monocytes and/or monocyte-derived macrophages. This is the first step in creating a method for assessment of macrophage activity, which is required for further development of immune-correcting drugs. The existing preliminary data provide the basis for realization of this idea.

Prevention through evaluation and treatment of cardiovascular risk factors is an efficient approach to reduce the risk of cardiovascular events, however, the problem remains that the available treatment options are underused. Implementation of cardiovascular disease prevention guidelines into clinical practice is therefore important for decreasing the burden of cardiovascular disease in general population. However, there are many barriers to this process, including questionable relevance of scientific results for clinical practice, personal preferences and expertise of the doctors, patient attitudes, lack of time, and economical factors. All these factors need to be taken into account for any change in the clinical practice to be successful. With respect to cardiovascular disease prevention, insufficient screening for risk factors, inappropriate risk estimation and hesitation to keep to the guidelines-based treatment targets contribute most to inadequate control of risk factors, and this has been repeatedly demonstrated to be difficult to improve. In this context, our studies demonstrate that the emphasis on systematic application of principles of cardiovascular prevention results in improved control of cardiovascular risk factors. Adequate support for transforming guidelines-based knowledge into practicable habit appears therefore important for successful prevention of cardiovascular disease in clinical practice and may translate into substantial reduction of cardiovascular risk in general population.

Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the "cholesterol hypothesis" that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes.

Atherosclerotic cardiovascular diseases are a worldwide major public health concern. Atherosclerosis is driven by a chronic inflammatory process which is present since the early stages of the disease, as a response to endothelium aggression by a variety of offending agents, to subsequent formation of foam cells, atheromatous plaque development and the clinical complications of the disease, due to plaque rupture and thromboembolic acute episodes. However, drug therapies directed to inflammation are lacking in the clinical practice, despite an increasing effort of research and identification of several potential molecular targets. Effective medical treatments available for primary and secondary prevention are restricted to cholesterol lowering statins and anti-platelet drugs such as aspirin. Here, steps of atherogenesis, cells involved in the process, secreted pro- and anti-inflammatory factors, the concept of unstable and stable atheroma plaques, the intertwining among inflammation, lipid arterial deposit, thrombus formation, therapeutically targetable mechanisms, monoclonal antibodies, enzymatic inhibitors, phytotherapeutic compounds and anti-proliferative agents used in cancer chemotherapy, drugs tested in experimental animals and at the clinical stage are shortly reviewed. Because statins and anti-platelet drugs use do not prevent more than 30-40% of the major cardiovascular events, the development of novel therapeutic tools is desirable. Nonetheless, atherosclerosis is a chronic process presumably demanding long-standing treatments, so that the safety, opportunity, cost-effectiveness and development of drug resistance are major issues that challenge the introduction of novel, inflammation-oriented therapies.

Epidemiological studies suggest that the cardioprotective properties of olive oil, particularly extra-virgin type, result from a positive influence of its components, such as phenolic compounds, on the cardiovascular system. One of the most abundant phenolic compounds of extra virgin olive oil is the dialdehydic form of elenolic acid conjugated with 3, 4-(dihydroxyphenyl)ethanol (3, 4- DHPEA-EDA), also known as oleacein. Due to its abundance in olive oil, it may play a special role in decreasing the progression of atherosclerosis. Some bioactivities of oleacein, such as antioxidant, anti-inflammatory, anti-proliferative and antimicrobial, were documented. There is also evidence of the bioavailability of oleacein in humans as well. However, due to the lack of clinical data, further studies are needed to provide information about the usefulness of this compound in antiatherosclerotic therapy.

Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a “natural” and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that “more-is-better”.

Statins reduce cardiovascular mortality and morbidity as well as cardiovascular events in patients with a very high risk of cardiovascular disease (CVD) and also in subjects with high or moderate risk by reducing the levels of low-density lipoprotein cholesterol (LDL-C). Although they are considered to be drugs with a very good safety profile, because of their wide use there are many concerns that their adverse effects might compromise their proven beneficial effects. Therefore this article reviews all the data and provides an evidence- based insight what are the proven adverse effects of statins and what are the “myths” about them. The most important side effects include myopathy and rhabdomyolysis. Another side effect is increased activity of liver tests which occurs occasionally and is reversible. However, recent studies even suggest that statin therapy can improve hepatic steatosis. It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk. Statin therapy has also been associated with some adverse renal effects, eg. acute renal failure, but recent data suggest even a possible protective effect of these drugs on renal dysfunction. Concerns that statins might increase cancer have not been proven. On the contrary, several studies have indicated a possible benefit of these drugs in patients with different types of cancer. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Systematic reviews and clinical guidelines suggest that the cardiovascular benefits of statins by far out-weight non-cardiovascular harms in patients with cardiovascular risk.

The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non-reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells.