Current Pharmaceutical Design - Volume 13, Issue 36, 2007

Atherosclerosis is a disease of multifactorial origin which represents a major global cause of morbidity and mortality. The presence of macrophages, as a major cell-type, in the atheromatous plaque and the role played by Toll-like receptors (TLRs) in its pathogenesis clearly support a robust immunological involvement in this disease. On these grounds, the present issue of Current Pharmaceutical Design, entitled: “Immune-Mediated Mechanisms in Atherosclerosis: Prevention and Treatment of Clinical Manifestations” will place emphasis on animal and human models of atherosclerosis, pathogenesis and clinical aspects, potential new drug targets and pharmacogenomics. Koppang and associates [1] will present, as an animal model of atherosclerosis, some immunophatological pictures of coronary disease in salmon which resemble those observed in humans. Lenato and associates [2] will describe some immune abnormalities found in hereditary haemorrahagic teleangiectasia, an autosomal dominant disease, and its relationship with atherosclerosis. Gibson and Genco [3] will demonstrate that Porphyromonas gingivalis accelerates atherosclerosis in hyperlipidemic mice and immunization is effective in the prevention of pathogen-induced atherosclerosis. Matarese and associates [4] will review the most recent advances on adipokine research and the link with atherosclerosis as an effect of low degree chronic inflammation typical of obesity and metabolic syndrome. Price and Knight [5] will illustrate the roles played by glycated proteins in atherosclerosis development through receptor-mediated release of progression factors, especially in diabetes. Misciagna and associates [6] will point out that non enzymatic glycation of protein in the blood is associated with cardiovascular disease also in non diabetic subjects, and could be used to define risk factors of cardiovascular disease. Amati and associates [7] will describe the immune bases of obesity and its prevention in order to reduce more serious complications in adulthood, even including atherosclerosis development. Niessner and associates [8] will discuss on the main therapeutic approaches to atherosclerosis, such as (1) immunomodulatory effects of existing therapies, (2) therapies targeting inflammatory triggers, and (3) agents inhibiting specific immune mechanisms. Tafaro and associates [9] will place emphasis on the effects on colostrum and milk from donkey on human peripheral blood mononuclear cells (PBMCs) and its use in the prevention of atherosclerosis. Magrone and associates [10] will demonstrate that a moderate assumption of red wine, as in vitro evaluated on human PBMCs, leads to a robust production of nitric oxide useful in the prevention of atherosclerosis. Candore and associates [11] will illustrate the application of pharmacogenomics in the prevention and cure of coronary heart disease, mostly, in terms of early identification of individuals susceptible to disease and discovery of potential targets for drugs. References [1] Koppang EO, Fischer U, Satoh M, Jirillo E. Inflammation in fish as seen from a morphological point of view with special reference to the vascular compartment. Curr Pharm Des 2007; 13(36): 3649-3655. [2] Lenato GM, Soppressa P, Giordano P, Guanti G, Guastamacchia E, Triggiani V, Amati L, Resta F, Covelli V, Jirillo E, Sabbà C. Hereditary Haemorrhagic Teleangiectasia: a rare disease as a model for the study of human atherosclerosis. Curr Pharm Des 2007; 13(36): 3656-3664. [3] Gibson III FC, Genco CA. Porphyromonas gingivalis mediated periodontal disease and atherosclerosis: disparate diseases with commonalities in pathogenesis through TLRs. Curr Pharm Des 2007; 13(36): 3665-3675. [4] Matarese G, Mantzoros C, La Cava A. Leptin and adipocytokines: bridging the gap between immunity and atherosclerosis. Curr Pharm Des 2007; 13(36): 3676-3680. [5] Price CL, Knight SC. Advanced glycation: a novel outlook on atherosclerosis. Curr Pharm Des 2007; 13(36): 3681-3687. [6] Misciagna G, De Michele G, Trevisan M. Non enzymatic proteins in the blood and cardiovascular disease. Curr Pharm Des 2007; 13(36): 3688-3695. [7] Amati L, Chiloiro M, Covelli V. Early pathogenesis of atherosclerosis: the childhood obesity. Curr Pharm Des 2007; 13(36): 3696- 3700. [8] Goronzy JJ, Weyand CM, Niessner A. Immune-mediated mechanisms in atherosclerosis: prevention and treatment of clinical manifestations. Curr Pharm Des 2007; 13(36): 3701-3710. [9] Tafaro A, Magrone T, Jirillo F, Martemucci G, D'Alessandro AG, Amati L, Jirillo E. Immunological properties of donkey's milk: its potential use in the prevention of atherosclerosis. Curr Pharm Des 2007; 13(36): 3711-3717. [10] Magrone T, Tafaro A, Jirillo F, Panaro MA, Cuzzuol P, Cuzzuol AC, Pugliese V, Amati L, Jirillo E, Covelli V. Red wine and prevention of atherosclerosis: an in vitro model using human peripheral blood mononuclear cells. Curr Pharm Des 2007; 13(36): 3718-3725. [11] Candore G, Balistreri CR, Caruso M, Grimaldi MP, Incalcaterra E, Listi F, Vasto S, Caruso C. Pharmacogenomics: a tool to prevent and cure coronary heart disease. Curr Pharm Des 2007; 13(36): 3726-3734.

Modern bony fishes or teleosts are increasingly being used as model organisms for human diseases. Ambitious mapping programmes have revealed parts of or entire genomes of several species. This information suggests that there are several similarities between the mammalian and teleost immune systems, but also important differences. These differences are especially evident in the anatomical and functional constructions. However, compared to mammals, morphological studies of the immune system and in particular the inflammatory responses in fish are scarce, much due to a general lack of good cell markers. This review seeks to give an overview of the current knowledge of the teleost immune system related to inflammation and morphological research. The emphasis is placed on coronary changes which may be observed in salmonids over the size of 10 cm. Here, the immunopathological picture has some resemblance to that observed in similar changes in humans.

Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler-Weber syndrome is an autosomal dominant disease characterized by local angiodysplasia affecting different organism districts. From a clinical viewpoint, HHT patients suffer from epistaxis, mucocutaneous telangiectases and arteriovenous malformations in various organs. Mutations in two known genes (ENG and ALK1) account for the majority of HHT patients. Additional loci are predicted, but the underlying genes are still to be identified. Moreover, SMAD4 mutations have been reported to cause JP-HHT combined syndrome. Both endoglin and ALK-1 bind to various growth factors in the context of the Transforming Growth Factors (TGF)-β superfamily and their expression is restricted to vascular endothelial cells and very few other cell types, such as activated monocytes. Endoglin and ALK1 mutations are thought to affect endothelial cell metabolism, angiogenesis and vascular remodelling, even if the precise mechanism leading to the HHT lesions is still obscure. Endoglin is also overexpressed in smooth muscle cells of atherosclerotic plaques, suggesting a role for this protein in atherogenesis and plaque progression, as well as in other cardiovascular diseases. Recently, we demonstrated that HHT adult patients display several deficits of both innate and adaptive immune system. Here, we investigated the function of immune cells in HHT pediatric patients. Our results clearly show that HHT children have a normal functionally immune system, and suggest that HHT patients become immunocompromised host during their lifetime, likely due to a precocious immunosenescence. Moreover, the relationship between immune responsiveness in HHT and atherosclerosis are discussed.

Toll-like receptors (TLRs) are a group of pathogen-associated molecular pattern receptors, which play an important role in innate immune signaling in response to microbial infection. It has been demonstrated that TLRs are differentially up regulated in response to microbial infection and chronic inflammatory diseases such as atherosclerosis. Furthermore hyperlipidemic mice deficient in TLR2, TLR4, and MyD88 signaling exhibit diminished inflammatory responses and decreased atherosclerosis. Accumulating evidence has implicated specific infectious agents including the periodontal disease pathogen Porphyromonas gingivalis in the progression of atherosclerosis. Evidence in humans suggesting that periodontal infection predisposes to atherosclerosis is derived from studies demonstrating that the periodontal pathogen P. gingivalis resides in the wall of atherosclerotic vessels and seroepidemiological studies demonstrating an association between pathogen-specific IgG antibodies and atherosclerosis. We have established that the inflammatory signaling pathways that P. gingivalis utilizes is dependent on the cell type and this specificity clearly influences innate immune signaling in the context of local and distant chronic inflammation induced by this pathogen. We have demonstrated that P. gingivalis requires TLR2 to induce oral inflammatory bone lose in mice. Furthermore, we have demonstrated that P. gingivalis infection accelerates atherosclerosis in hyperlipidemic mice with an associated increase in expression of TLR2 and TLR4 in atherosclerotic lesions. Our recent work with P. gingivalis has demonstrated the effectiveness of specific intervention strategies (immunization) in the prevention of pathogen-accelerated atherosclerosis. Improved understanding of the mechanisms driving infection, and chronic inflammation during atherosclerosis may ultimately provide new targets for therapy.

The role of the adipose tissue in immunity has recently emerged, and there is now ample evidence that this role is elucidated by a number of cytokine-like hormones produced by adipocytes - called adipokines. The most relevant adipokines are leptin, adiponectin and visfatin, and all have marked effects on metabolic and immune function. The discovery of adipokines has led to the development of a novel concept that the pathogenesis of atherosclerosis can be associated with low-degree inflammation associated with slow (auto)immune attack of the endothelial wall of arteries. This model considers therefore adipokines as the bridge between atherosclerosis, inflammation and immunity. We review here the most recent advances on adipokine research, with a particular emphasis on the model that considers atherosclerotic lesions as effects of the (auto)immune-mediated damage of the endothelium that is sustained by low-degree chronic inflammation typical of obesity and metabolic syndrome.

Atherosclerosis is a major global cause of morbidity and mortality, and diabetes patients are at increased risk of coronary heart disease development. Advanced glycation of proteins occurs in the body due to raised concentrations of reducing sugars and reactive oxygen species, and is a causal factor behind complications of diabetes. Glycated proteins, through alteration of protein structure and function, and from ligation with their receptors, lead to widespread vascular damage. The α-oxoaldehyde, methylglyoxal (MG) is the most reactive glycation precursor, and is increased in the blood of diabetes patients. There is debate about the triggering events leading to atherosclerosis, but the inflammatory action of glycated proteins, including those with MG adducts, through their receptor, RAGE, is a major candidate for initiating plaque formation. In addition glycation may cause cross-links on proteins of the extracellular matrix, stiffening arteries and ‘trapping’ other macromolecules. MG is also likely to form adducts on many other proteins, enzymes, lipids, DNA or RNA, changing their structure, and may disrupt enzyme activity, hormone regulation and immune function. In the latter context, MG disrupts function of the potent antigen presenting cells, dendritic cells. This effect may be a double edged sword: Poor control of infections may contribute to persistent inflammation, whilst inhibition of immune activation by dendritic cells may inhibit plaque progression. This review aims to present these ideas as a novel slant on the role of the glycation process in atherosclerosis.

The study of the role of glycemia in the causation of cardiovascular disease has been limited by several factors, above all by its measurement over time. Non enzymatic glycated proteins in the blood, the product of the non enzymatic reaction of a reducing sugar with the reactive amino acid of a target protein, are an integrated measure of blood glucose over days to weeks. They have been used in the management of clinical diabetes mellitus, but are still infrequently used in epidemiological studies in non diabetic subjects. There are few epidemiological studies that show that glycated hemoglobin, fructosamine, an index of total non enzymatic glycated proteins in the blood, and glycated apolipoprotein B and other non enzymatic glycated proteins in the blood in non diabetic subjects are associated with cardiovascular diseases. In this paper we review: 1) the overall mechanisms of non enzymatic glycation of proteins; 2) the measurement of glycated hemoglobin, fructosamine, and glycated apolipoprotein B and their relationship with blood glucose levels in non diabetic subjects; 3) the association of glycated hemoglobin, fructosamine and glycated apolipoprotein B with cardiovascular disease. We conclude that non enzymatic glycation of protein in the blood is associated with cardiovascular disease also in non diabetic subjects, and could be used to define dietary risk factors of cardiovascular disease.

Obesity represents a chronic inflammatory status and adipocytes release either cytokines or an array of adipokines such as leptin, endowed with immunomodulating and systemic activities. The involvement of cytokines in obesity as well as of the adipokine leptin is supported by the notion that weight reduction normalizes mediators of inflammation. In this framework, we will demonstrate that in obese children, subjected for a period of six months to a hypocaloric diet, reduction of major biochemical and anthropometric parameters correlates with a normalization of immune status. Infact, absolute numbers of CD4+ cells and CD4/CD8 ratio increase, while leptin values fluctuate within normal ranges, being this adipokine involved in the modulation of either innate or adaptive immune responses. In the discussion, the immune abnormalities detected in obesity will be pointed out and emphasis will be placed on the increased frequency of infectious episodes occurring in obese adolescent and adults. Finally, the infectious etiology of obesity will be illustrated in the sense that adipocytes interacting with infectious agents may cause obesity. Taken together, the bulk of available data indicate that childhood obesity should be prevented or reduced to avoid more serious complications in adulthood.

Accumulation of inflammatory cells identifies atherosclerotic plaque at risk for rupture. Typically, activated immune cells occupy the rupture-prone areas of the atherosclerotic lesion. These cells are an appealing therapeutic target for novel strategies of plaque stabilization. Biologic consequences of plaque inflammation ultimately depend not only on the cellular players populating the lesion but also on triggers of immune activation originating from within the plaque or arriving from the circulation, and immune effector mechanisms that mediate cellular damage and plaque destabilization. Recent studies have provided insights into particular immune mechanisms in the atherosclerotic plaque that contribute to plaque vulnerability. This knowledge provides the basis for potential immunomodulatory therapies in cardiovascular disease. These therapeutic approaches can be classified as (1) immunomodulatory effects of existing therapies, (2) therapies targeting inflammatory triggers, and (3) agents inhibiting specific immune mechanisms.

Donkey's milk is the best substitute of human milk for its content in lactose, proteins, minerals, and ω-3 fatty acids. Here, we have evaluated the effects of colostrum and milk from donkeys (Martina Franca breed) on the function of human peripheral blood mononuclear cells (PBMCs) at different intervals from lactation. Colostrum induced more IgA responses, while milk induced predominantly more IgG responses. Both milk and colostrum induced expression of CD25 and CD69 on PBMCs. The ability to induce release of interleukins (IL) (IL-12, IL-1β and IL-10) and tumor necrosis factor-α was confined only to milk, while colostrum was devoid of this capacity. Finally, both colostrum and milk induced nitric oxide (NO) release from PBMCs but milk exhibited a greater capacity than colostrum in NO generation. Taken together, these immunological activities exerted by both colostrum and milk from donkeys may be useful in the treatment of human immune-related diseases. In particular, NO induction by donkey's milk may be very useful in the prevention of atherosclerosis, being a strong vasodilator and an effective antimicrobial agent since pathogens and/or their products may play a proatherogenic role.

Evidence has been provided that red wine possesses antiatherogenic activities in virtue of its content in polyphenols (flavonoids and non-flavonoids substances). Here, some red wines (Negroamaro, Primitivo and Lambrusco) were tested for their ability to trigger nitric oxide (NO) production from human healthy peripheral blood mononuclear cells (PBMC). Negroamaro was the strongest inducer of NO from PBMC and deprivation of polyphenols did not influence its NO generation capacity. This fact supports the involvement of polyphenols in the NO production even in the absence of alcohol, which also per se does not exert any significant activity. These results are also corroborated by the evidence that PBMC inducible-nitric oxide synthase expression occured by the effect of samples containing polyphenols but this expression was very weak when polyphenols were removed from the whole Negroamaro. In synthesis, flavonoids and resveratrol, major constitutents of red wine, once absorbed at intestinal level, enter circulation and trigger monocytes for NO production. To the best of our knowledge, this is the first demonstration of a direct effect of red wine on monocytes for NO release to occur. On the other hand, also the macrophage contingent from gut-associated lymphoid tissue can contribute to NO generation, besides the aliquot produced by endothelial cells, as previously demonstrated by various authors. Taken together, these results support the concept that moderate intake of red wine can prevent atherosclerosis via production of NO, a potent vasodilator of terminal vessels.

Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). This is supported by epidemiological studies which have thoroughly investigated the association between CHD and gene polymorphisms of the inflammatory molecules. Moreover, efforts to find elective therapy have not been rewarding and, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. A critical search of published literature has suggested few inflammatory genes directly involved in the risk to develop CHD and MI. The selected genes are, the pro- and anti-inflammatory cytokines, Toll-like receptor 4 (TLR4), CD14, CCR5, cyclooxygenases (COXs) and lipoxygenases (LOXs). The associations between candidate gene polymorphisms and CHD/MI are difficult and complex as a consequence of pleiotropy, variations with age, selection due to the lethality of the disease, and interactions with other genes and environmental factors. However, current data indicate that screening for interleukin (IL)-6, IL-10, TLR4, CCR5, COX and LOX polymorphisms are likely to be a useful tool for CHD and MI risk assessment. What we believe is that dissecting out the influence of genetics polymorphism within the complex pathophysiology of CHD and MI will help to provide a more complete risk assessment and complement known classical cardiological risk factors. The detection of a risk profile will potentially allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug of lifestyle modification.