Cardiovascular & Haematological Disorders - Drug Targets - Volume 8, Issue 1, 2008

Coronary artery vasculopathy (CAV), characterized by diffuse concentric coronary artery intimal thickening with fibrosis, remains a significant complication impeding long term engraftment in heart transplantation. The pathophysiologic processes driving CAV are not well understood, however T cell mediated cellular immunity and cytokines have been implicated. The inability to prevent CAV may be related in part to a limited spectrum of inhibition that that current immunosuppressive therapies exhibit against second messenger pathways elicited by T cell receptor (TCR) activation and dose limiting toxicities. Therefore, considering that antigen specific T cell activation is initiated at the TCR, including alloresponses involving direct and indirect antigen presentation, targeting the proximal kinases involved in this process may provide novel therapeutic options for controlling rejection. Src family kinases (SFK), particularly p56lck (Lck) and p59fyn (Fyn), are intimately associated with the earliest signaling events through the TCR and could provide targets for immunomodulatory agents. Such targeted inhibition of TCR signaling may institute a novel approach for diminishing the T cell mediated response associated with CAV. In this review we discuss therapeutic agents that have been shown to inhibit SFK and the rationale for investigating the potential application of these agents in heart transplantation.

Studies performed during the last decade indicate that adipose tissue is not only a site of triglyceride storage but also an active endocrine organ which secretes many biologically active mediators referred to as “adipokines”. In contrast to many adipokines which are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism and cardiovascular system, such as leptin, tumor necrosis factor-α, plasminogen activator inhibitor-1, resistin, etc., adiponectin seems to be a unique adipokine which is produced in lower amounts in obese than in lean subjects and possesses predominantly beneficial activities, i.e. increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reaction and induces endothelium-dependent nitric oxide-mediated vasorelaxation. Adiponectin binds two receptors, AdipoR1 and AdipoR2. Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium-dependent vasorelaxation and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Raising endogenous adiponectin level or increasing the sensitivity to this hormone may be a promising therapeutic strategy for patients with metabolic and cardiovascular diseases. Among currently used drugs, thiazolidinediones (peroxisome proliferator activated receptor γ agonists) are most effective in elevating adiponectin level.

Reduction of infarct size as well as alleviation of other ischemia- and reperfusion-associated injuries are the goals of primary importance in cardiology. One of the remedies is considered to be myocardial preconditioning (PreCon) referred usually to as an increased myocardial tolerance to prolonged ischemia following brief ischemic or non-ischemic challenge. In this review, PreCon stimuli tested to date are considered including a number of mildly noxious factors applied either locally to the myocardium or systemically. Recently, one more mode of heart protection against reperfusion injury termed postconditioning (PostCon) has been developed. On the basis of ample evidence published, along with our findings, a detailed comparative analysis of PreCon and PostCon is presented, with special emphasis on the cellular, molecular, and pharmacological aspects of the topic as well as clinical applications, both implemented and awaiting practical approval.

The regulation of heart function is one of the essentials for the survival of organism. Therefore, the effective mechanisms of regulation can minimize the energy requirements and improve the ability to react to different needs on time and appropriately . Two receptor types, β-adrenoceptors and muscarinic receptors, with almost antagonistic function, are “basic regulators” of the heart parameters. It is relevant to mention that beside the main adrenoceptors and muscarinic receptors subtypes (β1- and M2-subtype), other minor subtypes that regulate heart function, i.e. β2-, β3-adrenoceptors, α1-adrenoceptors and minor subtypes of muscarinic receptors (M1, M3 and M5) are present in the heart. In this regard is intriguing that just two catecholamines (adrenaline, noradrenaline) have many “targets” - receptors that differ so much in the functional consequences of their activation: while β1- and β2-adrenoceptors cause cardiostimulation, β3-adrenoceptors are responsible for cardioinhibition and α1-adrenoceptors contribute to enhanced inotropy. Similarly, some data show that other muscarinic receptors than M2 muscarinic subtype, are expressed in the heart and these minor subtype(s) can contribute to the heart regulation in similar way as β3-adrenoceptors to the catecholamine action. Taken together, regulation of heart function through different receptor subtypes and using homologous and heterologous regulation can represent an effective tool for coping with permanently changing environmental conditions.

Inflammation underlies the pathogenesis of many common cardiovascular diseases (CVD) such as myocardial infarction, atherosclerosis, myocarditis and dilated cardiomyopathy. Allergic disorders like allergic rhinitis and asthma, both chronic inflammatory conditions, have recently been linked to increased CVD and death. Studies have found that increased IgE levels, eosinophilia, positive skin-prick tests, self-reported asthma and enzymes that regulate leukotriene synthesis (5-lipoxygenase) predict a high risk for atherosclerosis, stroke and myocardial infarction. Mast cells (MCs), cells involved in the pathogenesis of allergy and asthma, are emerging as key players in the regulation of inflammation and fibrosis in the heart and vasculature. Our laboratory has found that MC numbers are increased in mice susceptible to developing chronic dilated cardiomyopathy. The fibrosis associated with chronic heart disease is increased by MC degranulation. MCs can also act as antigen-presenting cells increasing inflammation in the heart through Toll-like receptor-4 signaling and increased proinflammatory cytokine production. Similar inflammatory mechanisms are observed for myocarditis and atherosclerosis. Many of the drugs currently used to reduce heart disease act on mediators/ pathways downstream of MC degranulation. An improved understanding of the role of MCs in regulating inflammation and fibrosis will enable researchers and clinicians to better treat heart disease.