Abstracts


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Macrophage Activation in Atherosclerosis: Pathogenesis and Pharmacology of Plaque Rupture
J.J. Boyle

Atherosclerosis is still an important disease. It accounts for 39% of deaths in the U.K. and 12 million U.S citizens have atherosclerosis-associated disease. Atherosclerosis may exert clinical effects by slow narrowing, producing stable angina or dramatic rupture, producing acute coronary syndromes such as unstable angina or myocardial infarction and death. Macrophages are abundant in ruptured atherosclerotic plaques. Macrophages are innate immune effectors, i.e. they are activated without antigenic specificity. This may make them liable to indiscriminate tissue damage, since they are less selective than lymphocytes. Macrophages are recruited and activated by many signals and have an impressive armamentarium of molecules to promote tissue damage. Macrophage recruitment by abnormal endothelium over developing atherosclerotic plaques, is aided by endothelial expression of adhesion molecules (ICAM-1, VCAM, ELAM). Use of knockout mice has implicated the chemoattractant cytokine (chemokine) MCP-1 in attracting macrophage recruitment in atherosclerosis. Macrophage-activation stimuli associated with atherosclerotic risk factors include oxidized low density lipoprotein (oxLDL, ‘bad cholesterol’), advanced glycosylation end products (AGEs) of diabetes, angiotensin II and endothelin. Substantial work has clarified macrophage activation by OxLDL via macrophage scavenger receptors (MSRs), especially MSRA and CD36. Activated macrophages express effector molecules that kill cells and degrade extracellular matrix. These include Fas-L and nitric oxide (NO). Macrophage NO is derived from the high output inducible nitric oxide synthase (iNOS) pathway and upregulates vascular smooth muscle (VSMC) cell surface Fas, priming them for apoptosis. Activated macrophages express surface Fas-L, similar to cytotoxic T-lymphocytes and natural killer cells. Since VSMCs promote plaque stability, VSMC apoptosis may promote plaque rupture. Macrophages express multiple metalloproteinases (e.g. stromelysin) and serine proteases (e.g. urokinase) that degrade the extracellular matrix, weakening the plaque and making it rupture prone. Macrophages secrete numerous other effectors including reactive oxygen species, eicosanoids, tumour necrosis factor alpha and interleukin-1. Macrophage-derived transforming growth factor beta promotes fibrosis. Existing cardiovascular treatments including angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, aspirin, cholesterol reduction agents especially statins may inhibit macrophages. The interaction of NO-donors with macrophages and apoptosis is complex and bifunctional. Traditional anti-inflammatory agents such as glucocorticoids and cyclophosphamide have very serious side effects and are probably inappropriate. Novel anti-inflammatory agents e.g. new immunosuppressives and anti-TNF therapy may have an improved cost-benefit ratio.


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Glucocorticoids and Vascular Reactivity
Shumei Yang and Lubo Zhang

Corticosteroid hormones play an important role in the control of vascular smooth muscle tone by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. Increased cortisol response has been associated with an increase in arterial contractile sensitivity to norepinephrine and vascular resistance. Glucocorticoids regulate vascular reactivity by acting on both endothelial and vascular smooth muscle cells. Both glucocorticoid receptor protein and mRNA have been identified in endothelial and vascular smooth muscle cells. In endothelial cells, glucocorticoids suppress the production of vasodilators, such as prostacyclin and nitric oxide. In vascular smooth muscle cells, glucocorticoids enhance agonist-mediated pharmacomechanical coupling at multiple levels. The effect of glucocorticoids on vascular reactivity is regulated by 11 β-hydroxysteroid dehydrogenase (11β HSD). The presence of 11β-HSD in many tissues suggests that it modulates the access of corticosteroids to their receptors at both renal and extra-renal sites. The two 11β-HSD isozymes catalyze the interconversion of cortisol and cortisone. Type 1 11β-HSD has bidirectional activity, while the type 2 mainly converts cortisol into cortisone, the biologically inactive form. Both type 1 and type 2 11β-HSD have been found in vascular endothelial and smooth muscle cells, suggesting that abnormal 11B-HSD expression may play a pathogenic role in the common forms of hypertension. In this article, we review possible mechanisms involved in the glucocorticoid-mediated potentiation of vascular reactivity, its regulation by 11β-HSD, and their physiological and pathophysiological significance.


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Inflammation and Coronary Artery Disease
Uichi Ikeda

Several evidences, ranging from in vitro experiments, pathologic analysis and epidemiologic studies, show that atherosclerosis is intrinsically an inflammatory disease. The plasma concentrations of interleukin-6 (IL-6) and its hepatic by-product, C-Reactive Protein (CRP), appear to reflect the intensity of occult plaque inflammation and by inference may determine the vulnerability of plaque rupture. The monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in initiating coronary artery disease by recruiting monocytes/macrophages to the vessel wall. This leads to the formation of atherosclerotic lesions and also increases the vulnerability of the plaque. Indeed, circulating IL-6 and MCP-1 levels are elevated in patients with acute myocardial infarction, and also in patients with unstable angina, but not in those with stable angina. The plasma IL-6 and MCP-1 concentrations are also increased after percutaneous coronary intervention (PCI), and late restenosis is correlated with an increase in IL-6 or MCP-1 concentrations after the procedure. This finding suggests that the expression of IL-6 and MCP-1 may not only be related to the instability of atheromatous plaques, but also to the formation of restenotic lesions after PCI. The development of drugs specifically targeted against IL-6 and MCP-1 may be useful in the prevention of plaque formation, myocardial infarction and restenosis.


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Role of Oxidative-Nitrostative Stress and Poly(ADP-ribose) Polymerase in Cardiovascular Pathophysiology
Pal Pacher

Dysregulation of nitric oxide (NO) and increased oxidative stress have been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide, which impairs cardiovascular function via multiple mechanisms including activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP), also known as poly(ADP ribose) synthetase (PARS). When activated by DNA single-strand breaks, PARP initiates an energy-consuming cycle by transferring ADP ribose units from NAD⁺ to nuclear proteins. This process results in rapid depletion of the intracellular NAD⁺ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death. Moreover, PARP is involved in the expression of various inflammatory genes and mediators that contribute to cardiovascular pathophysiology. Overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury, heart failure, stroke, shock and autoimmune b-cell destruction and diabetic complications. Recent studies have provided evidence that the neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy of various forms of cardiovascular injury. This issue focuses on the role of oxidative-nitrosative stress and PARP activation in cardiovascular disorders and on novel emerging therapeutic strategies offered by neutralization of peroxynitrite and by inhibition of the PARP in these pathological conditions.


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Structure and Function of Poly(ADP-ribose) Polymerase-1: Role in Oxidative Stress-Related Pathologies
Laszlo Virag

Poly(ADP- ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP- ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD+ into nicotinamide and ADP- ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NFkB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).


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Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends
Carlos M. Villalón, David Centurión, Luis Felipe Valdivia, Peter de Vries and Pramod R. Saxena

Migraine treatment has evolved into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5 hydroxytryptamine; 5 HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an i.v. infusion of 5 HT can abort migraine. In fact, 5 HT as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatriptan, naratriptan), which belong to a new class of drugs, the 5 HT_1B/1D/1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half life. In line with the vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT_1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5 HT_1D/5-ht_1F receptors). Moreover, selective agonists at 5 HT_1D (PNU-142633) and 5 ht_1F (LY344864) receptors inhibit the trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT_1B receptors. Finally, although the triptans are effective antimigraine agents producing selective cranial vasoconstriction, efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT₇ receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side effects.


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Role of Oxidative Stress in Development of Cardiovascular Complications in Diabetes Mellitus
Mohamed A. Haidara, Hanaa Z. Yasin, Moshira Rateb, Hania Ammar and Mahmoud A. Zorkani

Diabetes represents a serious risk factor for the development of cardiovascular problems such as coronary heart disease, peripheral arterial disease, hypertension, stroke, cardiomyopathy, nephropathy and retinopathy. Identifying the pathogenesis of this increased risk provides a basis for secondary intervention to reduce morbidity and mortality in diabetic patients. Hyperglycemia and protein glycation, increased inflammation, a prothrombotic state and endothelial dysfunction have all been implicated as possible mechanisms for such complications. A linking element between many of these phenomena could possibly be, among other factors, increased production of reactive oxygen species. Vascular endothelial cells have several physiological actions that are essential for the normal function of the cardiovascular system. These include the production of nitric oxide (NO), which regulates vasodilatation, anticoagulation, leukocyte adhesion, smooth muscle proliferation and the antioxidative capacity of endothelial cells. However, under conditions of hyperglycemia, excessive amounts of superoxide radicals are produced inside vascular cells and this can interfere with NO production leading to the possible complications. This article aims at reviewing the links between reactive oxygen species, diabetes and vascular disease and whether or not antioxidants can alter the course of vascular complications in diabetic patients and animal models. A possible beneficial effect of antioxidants might present a new addition to the range of secondary preventive measures used in diabetic patients.


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Endothelin and Oxidative Stress in the Vascular System
David M. Pollock and Jennifer S. Pollock

Both endothelin(ET)-1 and oxidative stress have been the subjects of intense investigation within the cardiovascular field over the past decade and a half, yet little is known about the precise relationship between these important modulators of vascular function. There is a firm evidence that ET-1 can stimulate the production of superoxide via NADPH oxidase activation, and at the same time, reactive oxygen species appear to stimulate ET-1 production. What is less clear is how these changes participate in the pathogenesis of vascular dysfunction. There is mixed evidence on whether oxidative stress plays a role in ET-dependent hypertension, however, a specific influence of ET-induced oxidative stress to reduce vascular reactivity is more convincing. The current review summarizes recent investigations into the relationship between ET-1 and oxidative stress and highlights several areas that require further investigation.


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Angiotensin II, Cell Proliferation and Angiogenesis Regulator: Biologic and Therapeutic Implications in Cancer
Elizabeth Escobar, Tatiana Sofía Rodriguez-Reyna, Oscar Arrieta and Julio Sotelo

Angiotensin II (ANG II) is the main effector peptide in the renin-angiotensin system. It is generated by the activation of Angiotensin I through the Angiotensin II Converter Enzyme (ACE II). ANG II has multiple physiologic effects that regulate vascular tone, hormone secretion, tissue growth and neural activity. It has systemic (endocrine) and local (paracrine and autocrine) effects, favoring cell growth and differentiation through four types of receptors from which types 1 and 2 (AT₁ and AT₂) are the most important. Stimulation of AT₁ leads to the activation of intracellular pathways that finally lead to vasoconstriction, inflammation and proliferation. The AT₂ receptor is mainly expressed in fetal tissue and scantly in the cardiovascular system under different circumstances. Its effects are opposite to those of the AT₁. The stimulation of AT₁ activates second messengers that lead to a rapid production of diacylglycerol and 1-4-5-inositol triphosphate, as well as to the activation of C protein. Several reports indicate that ANG II can induce neovascularization in experimental systems due to the expression of different growth factors such as angiopoietin 2, vascular endothelial factor, and its receptor, fibroblast growth factor, platelet derived growth factor, transforming growth factor b and epidermal growth factor. Other mechanisms associated with ANG II induced angiogenesis are nitric oxide synthase and metalloproteinase expression, as well as inflammation induction. Angiogenesis is a fundamental process to tissue repair and development, and it participates in several pathologic processes. In addition, the AT₁ receptor is expressed in many malignant neoplasms and its blockade through ECA II inhibitors and ANG II antagonists has shown antineoplastic activity as well as angiogenesis inhibition in tumoral experimental models. This review discusses the mechanisms by which ANG II participates in neoplastic and non-neoplastic tissue angiogenesis and its possible therapeutic implications.


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Role of Nitrosative Stress and Poly(ADP-ribose) Polymerase Activation in Diabetic Vascular Dysfunction
Jon G. Mabley and Francisco Garcia Soriano

Complications of diabetes rather than the primary disease itself pose the most challenging aspects of diabetic patient management. Diabetic vascular dysfunction represents a problem of great clinical importance underlying the development of many of the complications including retinopathy, neuropathy and the increased risk of stroke, hypertension and myocardial infarction. Hyperglycaemia stimulates many cellular pathways, which result in oxidative stress, including increased production of advanced glycosylated end products, protein kinase C activation, and polyol pathway flux. Endothelial cells produce nitric oxide constitutively to regulate normal vascular tone; the combination of this nitric oxide with the hyperglycaemia-induced superoxide formation results in the production of reactive nitrogen species such as peroxynitrite. This nitrosative stress results in many damaging cellular effects, but it is these effects on DNA, which are the most damaging to the cell function; nitrosative stress induces DNA single stand breaks and leads to over-activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). PARP activation contributes to endothelial cell dysfunction and appears to be the central mediator in all the mechanisms by which hyperglycaemia-induces diabetic vascular dysfunction. This review focuses on the mechanism by which hyperglycaemia induces nitrosative stress and the role PARP activation plays in diabetic vascular dysfunction.


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Atherogenesis in Renal Patients: A Model of Vascular Disease?
Georgios Efstratiadis, Konstantinos Tziomalos, Dimitri P. Mikhailidis, Vasilios G. Athyros and Apostolos Hatzitolios,

Chronic kidney disease (CKD), and particularly kidney failure, is associated with accelerated atherosclerosis and approximately a 20-fold increased risk of cardiovascular death. The majority of these patients die from complications directly attributed to atherosclerosis and their life expectancy is decreased. Established risk factors are involved in the pathogenesis of this phenomenon. Age, gender, smoking, hypertension, dyslipidaemia and diabetes mellitus are among the established risk factors. Inflammation, qualitative lipid disorders (e.g. small dense low density lipoprotein), vascular calcification and oxidative stress represent emerging risk factors. The precise mechanism of atherosclerosis in patients with kidney failure is not yet known. CKD might represent a clinical model of atherogenesis. Thus, the evidence obtained from investigating “renal” atherogenesis could be of interest in improving our understanding of this disease process in the non-renal population. We review the relationship between “renal” and non-renal atherosclerosis focusing on pathogenesis, risk factors and clinical events and how they interact with treatment options. Overall, the “later” stages of CKD may eventually be considered as a coronary heart disease equivalent condition.


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Endothelial Dysfunction, Impaired Endogenous Platelet Inhibition and Platelet Activation in Diabetes and Atherosclerosis
Andreas Schäfer and Johann Bauersachs

Platelet activation induces rapid thrombus formation at a ruptured atherosclerotic plaque leading to acute vessel occlusion and a fatal or non-fatal cardiovascular event. More recent evidence suggests that activated platelets play an additional central role during the initiation of atherosclerosis, essentially facilitating leukocyte adhesion and recruitment. Endothelial dysfunction is a common and early feature of cardiovascular diseases characterized by reduced bioavailability of prostacyclin and nitric oxide (NO). Subsequently impaired endogenous platelet inhibition causes platelet activation in pre-atherosclerotic vascular disease resulting in enhanced platelet susceptibility to agonists released from the inflamed endothelium. Platelet adhesion to inflammatory, dysfunctional endothelium precedes leukocyte adhesion. Indeed, adherent activated platelets are mandatory for leukocyte recruitment in the early phases of atherosclerosis under arterial flow conditions. Increased expression of chemokines in atherosclerotic plaques and the inflamed endothelium initiates and facilitates pro-inflammatory processes in leukocytes and the vascular wall. Apart from their chemotactic properties, some chemokines such as fractalkine contribute to platelet activation. Moreover, fractalkine induces leukocyte recruitment to inflamed endothelial cells under arterial flow by activating adherent platelets.

An aggressive form of atherosclerosis is found in patients with diabetes. Since diabetes is currently considered as a risk equivalent for coronary artery disease, the interaction between oxidative stress, endothelial dysfunction, impaired endogenous platelet inhibition and platelet activation is discussed in the light of diabetes. Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke.


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Amiodarone Hepatotoxicity
Mohamed Babatin, Samuel S. Lee and P. Timothy Pollak

Potential hepatotoxicity related to amiodarone therapy is often a concern when deciding whether to initiate or continue treatment with this medication. While mostly associated with long-term oral administration of the drug, toxicity has also been reported early during intravenous administration and months after discontinuation of therapy. In the majority of patients, it is discovered incidentally during routine testing of liver biochemistry and rarely do the hepatic effects develop into symptomatic liver injury or failure. Despite the widespread use of amiodarone, prospective clinical studies have been sparse and there has been little consensus among experts in the field regarding optimum monitoring for adverse effects in patients receiving this drug. In order to examine the current state of knowledge surrounding the incidence, pathogenesis and mechanism of liver effects associated with amiodarone, the existing literature was reviewed, with particular emphasis on clinical recommendations for monitoring.


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The Crosstalk Between Insulin and Renin-Angiotensin-Aldosterone Signaling Systems and its Effect on Glucose Metabolism and Diabetes Prevention
Giovanna Muscogiuri, Alberto O. Chavez, Amalia Gastaldelli, Luca Perego, Devjit Tripathy, Mario J. Saad, Licio Velloso and Franco Folli

Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulininduced nitric oxide (NO) production by activating ERK ½ and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin II-aldosterone systems and their role in glucose metabolism and diabetes prevention.


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Visceral Adipose Tissue and Atherosclerosis
Miina K. Öhman, Andrew P. Wright, Kevin J. Wickenheiser, Wei Luo and Daniel T. Eitzman

Obesity is a risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Recent studies have demonstrated that the vascular risk associated with obesity is correlated particularly with visceral adiposity. These clinical observations indicate that various adipose tissue depots may have differential effects on vascular risk. Cellular constituents of adipose tissue secrete cytokines and chemokines that may affect vascular disease. Visceral fat has been demonstrated to express more inflammatory cytokines than subcutaneous fat in obese states. The adipose tissue secretory profile may reflect the influx of macrophages that has been shown to occur with expansion of fat stores. This macrophage infiltration may lead to a chronic low grade, systemic, inflammatory state. Since circulating markers of inflammation are associated with cardiovascular events, the inflammation triggered by adipose tissue may contribute to increased vascular disease. While the vasculopathic effects of visceral obesity may be best treated by weight loss, long term weight loss is difficult to achieve, even with currently available pharmacotherapies. Therapies that target macrophage accumulation in fat or the adipocyte expression profile may be potentially beneficial in reducing the vascular risk associated with obesity. Further characterization of the factors responsible for promoting atherosclerosis in the setting of visceral obesity may lead to new targets for the prevention of atherosclerosis.


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Ginseng Compounds: An Update on their Molecular Mechanisms and Medical Applications Pp. 293-302
Jian-Ming Lü, Qizhi Yao and Changyi Chen

Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications. Ginsenosides, the major pharmacologically active ingredients of ginseng, appear to be responsible for most of the activities of ginseng including vasorelaxation, antioxidation, anti-inflammation and anti-cancer. Approximately 40 ginsenoside compounds have been identified. Researchers now focus on using purified individual ginsenoside to reveal the specific mechanism of functions of ginseng instead of using whole ginseng root extracts. Individual ginsenosides may have different effects in pharmacology and mechanisms due to their different chemical structures. Among them the most commonly studied ginsenosides are Rb1, Rg1, Rg3, Re, Rd and Rh1. The molecular mecha-nisms and medical applications of ginsenosides have attracted much attention and hundreds of papers have been published in the last few years. The general purpose of this update is to provide information of recently described effects of ginsenosides on antioxidation, vascular system, signal transduction pathways and interaction with receptors. Their therapeutic applications in animal models and humans as well as the pharmacokinetics and toxicity of ginsenosides are also discussed in this review. This review concludes with some thoughts for future directions in the further development of ginseng compounds as effective therapeutic agents.


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The Role of Trimetazidine After Acute Myocardial Infarction
Maciej Banach, Jacek Rysz, Aleksander Goch, Dimitri P. Mikhailidis and Giuseppe M.C. Rosano

“Metabolic treatment” involves the use of drugs to improve cardiomyocyte function. Trimetazidine is the most investigated drugs in this group. The ESC 2006 guidelines on the management of patients with stable angina mention the efficacy of metabolic treatment in improving physical efficiency and decreasing the recurrence of pain. The available data suggest that combined therapy of trimetazidine and haemodynamic drugs is an effective antianginal treatment that reduces the risk of pain recurrence (in as many as 64% of patients). The most recent studies also suggest that trimetazidine might be effective in patients with acute coronary syndromes, ischemic cardiomyopathy and heart failure. However, while trimetazidine has shown beneficial effects on surrogate endpoints in several small trials its effect on cardiovascular events is uncertain. Further large randomized studies are needed before its effects on cardiovascular events can be evaluated.


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Resistance to Aspirin and Thienopyridines in Diabetes Mellitus and Metabolic Syndrome
Giovanni Anfossi, Isabella Russo and Mariella Trovati

Platelets from patients affected by diabetes mellitus and metabolic syndrome show an impaired sensitivity to physiological antiaggregating agents and an enhanced activation state, mirrored by an increased expression of membrane activation markers; furthermore, they are more prone to form spontaneous microaggregates with ADP receptor involvement. These abnormalities are responsible for a pro-thrombotic condition, contributing to a high cardiovascular risk. This pattern of platelet abnormalities provides a strong rationale for aggressive antiplatelet therapy strongly recommended by guidelines both in diabetes mellitus and in metabolic syndrome, not only in the setting of acute coronary syndromes, but also for the long-term prevention of the cardiovascular events. Antiplatelet therapy in these pathological conditions, however, is still a matter of intense debate, especially because a high prevalence of “resistance” to these drugs (and to aspirin in particular) has been described in these patients. This may result in non-significant reductions in cardiovascular events. Different factors seem to be involved, including: i) genetic polymorphisms; ii) hyperglycemia and poor metabolic control; iii) reduced sensitivity to nitric oxide; iv) a pro-inflammatory and/or pro-thrombotic status, and, v) increased oxidative stress. This review will take into consideration: i) the results of the most relevant studies addressing the effects of the anti-aggregating treatment in patients affected by diabetes mellitus and/or metabolic syndrome, and, ii) the biochemical mechanisms accounting for the impaired sensitivity to aspirin and thienopyridines in the above mentioned clinical conditions.


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Mitochondrial MMP Activation, Dysfunction and Arrhythmogenesis in Hyperhomocysteinemia
Karni S. Moshal, Naira Metreveli, Iuliana Frank and Suresh C. Tyagi

Chronic volume/pressure overload-induced heart failure augments oxidative stress and activates matrix metalloproteinase which causes endocardial endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial systolic and diastolic function. The elevated levels of homocysteine (Hcy), hyperhomocysteinemia (HHcy),are associated with decline in cardiac performance. Hcy impairs the EM functions associated with the induction of ventricular hypertrophy leading to cardiac stiffness and diastolic heart failure. Hcy-induced neurological defects are mediated by the NMDA-R (N-methyl-D-aspartate (NMDA) receptor) activation. NMDA-R is expressed in the heart. However, the role of NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of NMDA-R attenuates NMDA-agonist-induced increase in the heart rate. Hcy increases intracellular calcium and activates calpain and calpain-associated mitochondrial (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization and uncoupling in the pathological setting is fueled by redox stress and calcium mishandling. Recently the role of cyclophilin D, a component of the mitochondrial membrane permeability transition pore, has been identified in cardiac-ischemia. Mechanisms underlying the potentiation between NMDA-R activation and mitochondrial defects leading to cardiac dysfunction during HHcy remain to be elucidated. This review addresses the mitochondrial mechanism by which Hcy contributes to the decline in mechano-electrical function and arrhythmogenesis via agonizing NMDA-R. The putative role of mitochondrial MMP activation, protease stress and mitochondrial permeability transition in cardiac conduction during HHcy is discussed. The review suggests that Hcy increases calcium overload and oxidative stress in the mitochondria and amplifies the activation of mtMMP, causing the opening of mitochondrial permeability transition pore leading to mechano-electrical dysfunction.


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Statins for the Prevention of First or Recurrent Stroke
Vasilios G. Athyros, Anna I. Kakafika, Konstantinos Tziomalos Athanassios A. Papageorgiou and Asterios Karagiannis

This review considers the evidence showing that statins can prevent first or recurrent stroke or improve its outcome in subjects at moderate or high risk for cardiovascular disease (CVD). Data are reviewed according to trial design (observational or prospective) and baseline CVD risk. Two (ASCOT, CARDS) out of five primary CVD prevention statin trials showed a considerable reduction in stroke rates. In two (MIRACL and PROVE IT) out of five acute coronary syndrome trials, the prevention of first stroke was significant. Most secondary prevention trials (4S, CARE, LIPID, HPS, GREACE and TNT) showed a beneficial effect of statins in stroke prevention. Finally, SPARCL, the only secondary stroke prevention trial in subjects without overt coronary heart disease (CHD), showed a significant reduction in total and ischaemic (fatal and nonfatal) stroke rate, although a small but significant increase in nonfatal haemorrhagic stroke was noted. There was also a significant reduction in CHD-related events. The possible mechanisms responsible for statin-associated stroke prevention are discussed. The evidence suggests the need to consider early and long-term statin treatment (with substantial low-density lipoprotein cholesterol reduction) in all patients at high risk of any type of major vascular event, without discriminating CHD from stroke. Thus, statins may be beneficial to both the heart and the brain.