Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 7, Issue 3, 2008

Atherosclerosis represents a very high-cost disease and its complications are the first cause of death in most of the industrialized countries. Observational and epidemiological data have suggested the potential role of fibrinogen and Creactive protein in coronary artery disease (CAD) development and progression. In addition, the evaluation of markers of infection and inflammation may be of importance for an effective prevention of cerebro-vascular risk too. Based on these evidences, the National Cholesterol Education Program, through the Adult Treatment Panel III Guidelines, identified these markers as emerging cardiovascular risk factors. However, the exact role of inflammation in atherosclerosis is still on debate. Several studies have reported an association between exposure to different inflammation agents and the incidence of CAD; these data derive almost exclusively from cross-sectional or retrospective studies that cannot establish a temporal relation between exposure to inflammation and CAD. Recent studies have been also focused on the role of markers of inflammation on subclinical atherosclerosis. Further, the strong association of inflammation with cardiovascular outcomes and its influence on the pathogenesis of vascular diseases raised the possible role of anti-inflammatory therapy for reducing cardiovascular risk. Future prospective studies are needed to test whether this fascinating approach of cardiovascular prevention will affect vascular outcomes or not.

In the vascular wall of large arteries, cellular and humoral immune responses are elicited as a consequence of diverse noxious stimuli within subendothelial space, which further derives in endothelial dysfunction, the accumulation of lipids and formation of the atheromatous plaque. Monocytes, macrophages, T cells, endothelial cells and smooth muscular cells are all players in this inflammatory-atherosclerotic process, which is not only genetically regulated but also influenced by environmental factors. In this review, the summary of genetic variants in major immune mediators associated with the evolution of atherosclerosis is presented.

Oxidative stress is a result of an imbalanced equilibrium between reactive oxygen species (ROS) generation and their elimination by antioxidants. There is substantial evidence indicating that exacerbated oxidative stress is relevant for the development of atherosclerosis and its associated complications, especially cardiovascular disease (CVD). According to the oxidative modification hypothesis, oxidised low density lipoproteins (LDL) induce atherosclerosis by triggering an inflammatory cascade within the vascular wall. This process can be inhibited or delayed by the antioxidative and antiinflammatory actions of high density lipoproteins (HDL). Clearly, paraoxonase-1 (PON1) is one of the most important contributors to the antioxidative capacity of HDL. Atherogenic dyslipidemia, oxidative stress and inflammatory conditions induce dramatic changes in HDL composition that considerably alters or attenuates HDL's anti-atherogenic effects. Such impairment of HDL's functions provides an important link between oxidative stress and inflammation in the pathogenesis of atherosclerosis. This review summarises and discusses the possible synergistic effects of dyslipidemia, oxidative stress and inflammation in promoting atherosclerosis and its complications, as well as potential benefits of therapeutic modulation of HDL's atheroprotective activity.

Immune mechanisms play a role in destabilization of atherosclerotic plaque. Vulnerability of the plaque depends on the features of lipid core, stability of the fibrous cap, macrophage and neutrophil infiltration. Also products of leukocytes like metalloproteinases and myeloperoxidase may destabilize the plaque. Destabilized plaque easily ruptures event after minor impact. After plaque rupture, when myocardial infarction happens, immune mechanisms play a role not only in healing, but also may destructively influence left ventricle remodeling. Tumor necrosis factor-α, transforming growth factor-β, toll like receptors and cyclooxygenase are among the most investigated molecules that are thought to influence left ventricular remodeling nowadays. Also autoimmunity (antibodies against contractile proteins) adversely contributes to myocardial remodeling.

Type 2 diabetes and obesity are major risk factors for the development of coronary artery disease (CAD), and premature atherosclerosis. Both conditions are associated with insulin resistance, oxidative stress, and inflammation. Several factors that increase the risk of cardiovascular disease tend to cluster together in the same individual. Insulin resistance is believed to be a pathophysiological disturbance that underlies many of risk factors. Whether insulin resistance per se is a cardiovascular risk factor, is uncertain. Besides insulin resistance of myocardial muscle both in patients with type 2 diabetes and in non diabetic subjects with angiographically proven CAD, then is also a mismatch between the redistribution of blood flow and glucose uptake during insulization in diabetic patients. Also, the endothelial dysfunction and the hyperinsulinemia that accompany insulin resistance may adversely affect myocardial function. In metabolic tissues, insulin signaling via the phosphatidylinositol 3-kinase pathway (predominant in the metabolic tissues) leads to glucose uptake and is down-regulated. The other pathways of insulin-receptor signaling being a growthfactor like pathway (mediated by MAPk) is upregulated and its continued activity leads to atherosclerosis. This review will focus on the relationship between insulin resistance, inflammation and atherosclerosis in patients with type 2 diabetes and metabolic syndrome. It will also address the metabolic consequences of the insulin resistance syndrome and the impact of insulin resistance on process of atherosclerosis including insulin signaling in cells of the vasculature.

Communities all over the world are confronted with an alarming rise in the rates of obesity, physical inactivity, and associated metabolic diseases. Central adiposity seems to go hand-in-hand with established risk factors like elevated blood pressure, dyslipidemia, and hyperglycemia. Although genetic and environmental influences modulate the ultimate risk, this clustering of chronic insults to the endothelium takes its toll in the form of atherothrombotic cardiovascular events. Insulin resistance, accepted as the underlying etiology of type 2 diabetes, appears to have other deleterious consequences, even in the absence of hyperglycemia. In 1988 Gerald Reaven advocated insulin resistance to be the core defect in his description of ‘syndrome X’, subsequently renamed as the currently-accepted ‘metabolic syndrome’ and identified by diagnostic criteria intended for clinical use. In recent years there has been an explosion of basic and clinical research pertaining to the metabolic syndrome, generating intense interest and controversy. The cellular and vascular accompaniments have shed some light into its pathophysiology. Heightened, low-grade inflammation as well as a continuum of vascular insults from endothelial dysfunction to advanced atherosclerosis has been studied in the context of the syndrome. Inflammatory biomolecules have been speculated be markers and mediators of oxidative stress and endovascular toxicity. Creactive protein has been the most extensively studied. ‘Adipocytokines’ are inflammatory agents that originate from adipose tissue, thus changing the concept that fat is a metabolically active organ rather than inert tissue. The effect of lifestyle interventions and pharmacologic agents is being investigated. Further research promises to elucidate the complex pathogenetic dynamics at play in the metabolic syndrome and lead to possible therapeutic opportunities.

Periodontal and atheromatous diseases affect a large proportion of the general population. They have been associated with each other and may be causally linked. It has not proved possible to confirm a causal relationship between periodontitis and atherosclerosis to date and contradictory results have been published, likely due to the multi-factorial nature of these diseases. The Medline database (PubMed) was explored for papers published in English, using a wide search strategy. This review discusses pathophysiological hypotheses on the possible link between atherosclerosis and periodontitis and analyzes the direct effect on the vascular endothelium of periodontopathogens, biochemical markers of chronic inflammation, pro-inflammatory cytokines and the role of atherogenic proteins in periodontitis. The article includes crosssectional, case-control, longitudinal, and interventional studies, and describes the latest meta-analyses published in the literature. Scientific evidence to date indicates that periodontitis is a risk factor for atherosclerosis, but longitudinal studies of large samples are required to determine whether there is a causal relationship between these diseases.

Atherosclerosis has been recognized as an inflammatory disease. The innate and adaptive immunity mechanisms are involved in atherogenesis. Low-grade inflammation is associated with innate immunity activation. The CRP has been proposed as the best indicator of low-grade inflammation and a predictor of cardiovascular events. A triumvirate of targets in the prevention of CVD are: LDL-C aggressive lowering, HDL-C increasing and CRP lowering. The statins' role in lipids and CRP lowering is well established. Moreover, statins may be beneficial in many other inflammatory immune conditions. Among PPAR-α agonists, anti-inflammatory properties of fenofibrate are the best demonstrated. PPAR-γ agonists (thiazolidinediones) pleiotropic effects are also promising. PPAR α/γ agonists have been proved to cause severe side effects. Ezetimibe exerts beneficial anti-inflammatory actions when administered with statins. Colesevelam, a novel bileacid sequestrant has beneficial lipid-lowering and anti-inflammatory actions. CETP and ACAT inhibitors actions call for further studies. Inhibition of CRP, CRP-targeted antisenses, HDL-particle modification and immunomodulation of atherosclerosis are possible novel approaches in atherosclerosis treatment and prevention.

Atherosclerosis is a major vascular complication of diabetes and the primary cause of mortality in patients with this disease. Inflammation has been implicated in the pathogenesis, progression and complications of both atherosclerosis and diabetes type 2, and these two complex disorders are often found intertwined in the patients. Peroxisome proliferatoractivated receptors-γ (PPARs-γ) are nuclear receptors that have been involved as transcriptional mediators in glucose homeostasis, lipid metabolism, and adipogenesis. PPAR-γ agonists, the thiazolidinediones (TZDs) are antidiabetic drugs that increase insulin sensitivity, lower blood glucose, decrease triglycerides and free fat acids and seem to have antiinflammatory effects as they reduce inflammatory markers and improve cardiovascular risk factors. All the major cell types in the vasculature express PPAR-γ including macrophages and vascular smooth muscle found cells in human atheroma. Activation of PPAR-γ by thiazolidinediones blocks vascular smooth muscle cells growth and migration thus reducing atherosclerosis. Several clinical studies have illustrated the beneficial role of thiazolidinediones in the atherosclerosis process, as they ameliorate endothelial dysfunction, reduce intima media thickness (IMT) in the carotid arteries and the restenosis rate after coronary stent implantation. However, recent trials have raised significant concerns about the deleterious action of thiazolidinediones, particularly rosiglitazone, on the cardiovascular system. Weighing the potential beneficial and harmful role of thiazolidinediones and exploring the possible mechanisms may provide a thorough view about the optimum clinical use of these compounds.

Numerous studies have demonstrated that diabetes associated hyperglycemia creates favourable conditions for overproduction of reactive oxygen species and the development of oxidative stress. Indeed, there is an increase of oxidative stress even at early stages of diabetes in children and adolescents. The results of recent studies suggest that excessive release of superoxide and hydrogen superoxide are responsible for intracellular activation of several intracellular pathways and alter the expression of genes in vascular cells that contribute to the pathogenesis of late diabetic complications. It has been demonstrated in experimental and clinical studies that high blood glucose concentration itself and related reactive oxygen species overproduction may alter endothelial cells structure and function and accelerate the initiation and progression of atherosclerosis. Because of its long history of proven efficacy and safety, gliclazide, a second generation sulfonylurea, is still widely used in monotherapy or in combination with other hypoglycemic agents. Beyond effective glycemic control, gliclazide appears to have extra-pancreatic effects, apparently independent of blood glucose lowering properties,. It has been demonstrated that gliclazide reduces proinflamatory markers, endothelial dysfunction, and platelets activity. These beneficial effects are likely mediated through the antioxidant properties of the drug. It seems that these unique features of gliclazide account for its capacity to inhibit the progression of atherosclerosis. Whether these properties translates into the ability to prevent the high incidence of cardiovascular morbidity and mortality in diabetic patients remains to be investigated.

Dating back to the early 1900's, clinical observations have pointed towards an intimate relationship between dyslipidemia, inflammation, and endothelial dysfunction in the pathogenesis of atherosclerosis. Despite a focus on aggressive lowering of low-density lipoprotein cholesterol (LDL-C) in patients at risk for developing cardiovascular disease, only moderate reductions in cardiovascular events have been achieved, suggesting other targets of therapy should be investigated. Over the past two decades pre-clinical and clinical data have demonstrated a direct correlation between inflammation and atheroma development. This review provides a detailed understanding of inflammation in atherogenesis with a particular emphasis on clinical studies correlating markers of inflammation with plaque progression using carotid intima-media thickness measurements and intravascular ultrasound.