Current Signal Transduction Therapy - Volume 7, Issue 2, 2012

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Reactive oxygen species (ROS) are involved in cardiovascular diseases and, in particular, in myocardial ischemia and reperfusion. Although the restoration of blood flow is essential for salvation of ischemic heart, reperfusion elicits itself additional tissue damages. This condition has been defined as myocardial-reperfusion injury. ROS have been firstly studied for their deleterious role during reperfusion, including protein oxidation, DNA strand breaks, lipids peroxydation or opening of mitochondrial permeability transition pore, that are all potentially harmful for the cell survival. Indeed, ROS are massively generated at the onset of reperfusion, contributing to the post-ischemic oxidative stress and mitochondrial dysfunction and ultimately leading to cardiomyocyte death. Animal studies using antioxidant treatments have shown beneficial and encouraging effects in myocardial ischemia-reperfusion. However, univocal interpretations of the results from clinical trials remain uncertain and controversial. Recently, another role of ROS had been highlighted. Multiple evidences had shown that ROS act as essential mediators of cardioprotection, mainly during pre- and post-conditioning. Thus, free radicals in myocardial ischemia reperfusion injury may be not considered just as detrimental but also as protective molecules. This review summarizes recent findings about this dual role of ROS in myocardial ischemia-reperfusion injury.

High density lipoproteins have a well-established, negative correlation with risk of cardiovascular disease. There is currently particular interest in trying to exploit this relationship by raising serum high density lipoprotein cholesterol to lower risk. More recent studies suggest that high density lipoproteins have a more widespread impact on cardiovascular pathophysiology, beyond its involvement in cholesterol metabolism. The lipoprotein influences the functioning of endothelial cells and cardiomyocytes in a manner suggesting a protective effect under conditions of physiological stress. On-going studies are investigating the magnitude of the influence of the lipoprotein on cell function, notably be defining the signalling pathways that are involved. Advances in this area will be discussed in the following review. These studies may identify new avenues that can be explored as potential targets to treat cardiovascular disease. A logical extension is to consider the high density lipoprotein complex itself as a potential therapeutic. In this respect the ability to synthesise artificial high density lipoproteins with functional properties of the native lipoprotein complex is a particularly attractive option. Such studies have already been initiated, as will be discussed below.

Acute atherosclerotic complications, such as myocardial infarction, are often provoked by the rupture of an atherosclerotic plaque and the subsequent thrombotic occlusion of the arterial lumen, which interrupts the blood flow and renders ischemic the downstream peripheral tissue. Several inflammatory mediators (including cytokines, chemokines and matrix metalloproteases) have been shown to orchestrate common pathophysiological mechanisms regulating both plaque vulnerability and myocardial injury. In particular, the selective activation of certain protective intracellular signaling pathways might represent a promising target to reduce the dramatic consequences of an ischemic cardiac event. In the present review we will update evidence on the active role of intracellular kinase cascades (such as mitogen-activated protein kinases [MAPKs], Akt, Janus kinase [JAK]-signal transducer and activator of transcription [STAT]) to reduce the global patient vulnerability for acute myocardial infarction.

Renin-angiotensin system (RAS) plays many roles in human physiology and its abnormal activation is certainly involved in various cardiovascular diseases such as hypertension and atherosclerosis: this is repeatedly confirmed by trials with RAS blockers in different clinical situations. In the last decade the classical circulating RAS has been flanked by new pathways with recently discovered players demonstrating not only an endocrine system, but also a paracrine and an intracrine system. New receptors (AT2, Mas, AT4, and receptor for renin and prorenin), new enzymes (angiotensinconverting enzyme 2, endopeptidase, aminopeptidases), new angiotensins (angiotensin III, angiotensin IV, angiotensin-[1- 7]) have been found. The most intriguing new aspect is represented by the presence of pathways which exert opposite effects with respect to the renin-angiotensin-AT1 receptor pathway: therefore it seems that RAS has an internal way to counterbalance the potentially negative actions. Atherosclerosis, the main cause of death in western countries, is a chronic inflammatory disorder at the vascular level with a well established sequence of cellular and tissue activation. The favourable modulation of RAS may represent a new and very promising way to interfere with the atherosclerotic process. The present review will try to give a complete update of RAS with its new and diverse physiological functions and will suggest the targets for the development of new drugs devoted to an effective prevention of cardiovascular atherosclerotic events.

Adrenergic receptor signaling and heart failure are inextricably linked. Beta-adrenergic receptors (β-ARs) serve not only as physiological modulators of heart rate and contractility, they are also primary therapeutic targets of individuals with heart failure as well as many other cardiovascular disorders. In light of these relationships, this short review will focus on the basic pharmacology distinguishing adrenergic receptor subtypes; on receptor subtype selective signaling; the molecular basis of β-AR gene expression; and, delve briefly into genetic variation of ??-ARs that represents a potential basis of differential natural history of heart failure progression and that may serve as an underlying basis for therapeutic response.

The last two decades have witnessed a growing number of experimental observations regarding the mineralocorticoid physiopathology, leading to a new understanding of the molecular basis of the aldosterone-induced target organ damage. As a matter of fact, although it has long been known that the combined administration of mineralocorticoids and salt leads to extensive vascular lesions in the target organs, the recognition that aldosterone is able to induce direct toxic effects on the various cell types that make up the cardiovascular organ has built up recently. Moreover, non-genomic effects have been attributed to aldosterone, i.e. effects which do not depend on the activation of the cellular transcription machinery, whose physiopathologic relevance is still being investigated. These advances in our understanding of aldosterone physiopathology have shed light on the biological reasons which are at the base of the impressive results obtained in clinical trials of aldosterone antagonism.

The role of C-reactive protein (CRP) as a mediator of atherogenesis/atherothrombosis, and, thus, as a potential therapeutic target to fight cardiovascular disease (CVD) is still elusive. In this review, we focus on CRP as a potential mediator of CVD analysing CRP signalling data derived from relevant in vitro and animal models related to inflammation, endothelial dysfunction, primary, and secondary haemostasis, all representing pathophysiological events of recognised importance in CVD. If in vitro studies appear to make a strong case of CRP as a proatherogenic/ prothrombotic molecule through nuclear factor-kappa B (NFκB) and peroxisome proliferator-activated receptor gamma (PPARγ) pathways, animal studies as well as human mendelian randomisation studies do not corroborate those in vitro observations. Several explanations might account for this discrepancy, but CRP contamination with biologically active compounds, such as bacterial compounds or sodium azide, remains an important potential confounding factor. Therefore, knowing whether CRP is a mediator of atherogenesis and CVD or just an innocent bystander reflecting the degree of unspecific systemic inflammation will most likely remain debated until the completion of clinical randomised controlled trials using selective inhibitors of CRP. This in turn prompts questions about whether CRPreducing agents will prevent atherogenesis-related complication in humans.

Repulsive guidance molecules (RGMs) are a group of glycosylphosphatidylinositol (GPI)-linked cellmembrane- associated proteins recently described. RGM family members play a diverse role in axonal guidance during embryo development, neuronal cell adhesion and regulation of systemic iron metabolism. Another important role of the RGM family, discovered recently, is that they act as co-receptors of bone morphogenetic proteins (BMPs), a group of proteins that are involved in bone development and the differentiation and progression of cancer. This indicates the potential impact of RGMs on cancer. The current review discusses the present knowledge on RGMs, their roles in BMP signalling and their potential implication in development and progression of cancer, particularly in the BMPs related bone metastasis.

Hematopoietic progenitor and stem cells (HPSCs) have been employed in cell-based therapy (CBT) to promote neovascularisation and regeneration of ischemic organs, such as heart and limbs. Furthermore, endothelial progenitor cells (EPCs) may favour tumour growth and adverse vascular targeting treatment by incorporating into neovessels. CBT is hampered by the paucity of HPSCs harvested from peripheral blood and suffers from several pitfalls, including the differentiation outcome of transplanted cells and low percentage of engrafted cells. Therefore, CBT will benefit of a better understanding of the signal transduction pathway(s) which drive(s) HPSC homing, proliferation and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to combat tumoral neovascularisation. The elevation in intracellular Ca2+ concentration is the key signal in the regulation of cellular motility, replication, and differentiation. Intracellular Ca2+ waves regulate cytoskeleton re-organisation and disassembly at focal adhesions, thus stimulating migration and substrate adhesion, and induce DNA transcription by recruiting Ca2+-sensitive transcription factors. However, the Ca2+ signalling toolkit which underlies Ca2+ release from intracellular stores and Ca2+ entry across the plasmalemma in HPSCs is still unclear. Our recent work has shown that the so-called store-operated Ca2+ entry stimulates EPC growth. Unravelling the mechanisms guiding HPSC behaviour might supply the biological bases required to improve CBT. For instance, genetic manipulation of the Ca2+ signalling machinery (such as transfer of genes encoding for the Ca2+ channels involved in EPC proliferation) could provide a novel approach to increase the extent of limb neovascularisation and regeneration of damaged hearts.

Insulin resistance (IR) is defined as a decreased response of peripheral tissues to insulin. It is a common cause of cardiovascular and hepatic diseases, and often precedes the onset of hyperglycemia and predicts the development of type 2 diabetes. Free fatty acids (FFA), inflammation and oxidative stress play key roles in the development and/or progression of IR induced by obesity. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily; PPAR agonists can improve IR by regulating glucose and lipid metabolisms, and by inhibiting inflammatory and oxidative stress responses. In the article, we will review the pathogenesis of obesity-induced IR, its therapeutic targets: PPARα/γ, and discuss the signal transduction pathways through which these drugs exert therapeutic effects.