Current Pharmaceutical Design, Vol. 12, #36, 2007

abstracts for 4 of the 11 articles

Early Pathogenesis of Atherosclerosis: The Childhood Obesity
L. Amati, M. Chiloiro, E. Jirillo and V. Covelli

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.

Inflammation of the gums has been known for at least 10 years as statistically relevant to atherosclerosis—jk

Porphyromonas Gingivalis Mediated Periodontal Disease and Atherosclerosis: Disparate Diseases with Commonalities in Pathogenesis Through TLRs
F.C. Gibson III and C.A. Genco

Toll-like receptors (TLRs) are a group of pathogen-associated molecular pattern receptors, which play an important role in in-nate 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 in-flammatory 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.

Leptin and Adipocytokines: Bridging the Gap Between Immunity and Atherosclerosis
G. Matarese, C. Mantzoros and A. La Cava

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.

Advanced Glycation: A Novel Outlook on Atherosclerosis
C.L. Price and S.C. Knight

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.

Immune-Mediated Mechanisms in Atherosclerosis: Prevention and Treatment of Clinical Manifestations
J.J. Goronzy, C.M. Weyand and A. Niessner

Accumulation of inflammatory cells identifies atherosclerotic plaque at risk for rupture. Typically, activated immune cells oc-cupy 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.