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How hyperglycemia promotes atherosclerosis: molecular mechanisms
Doron Aronson, Elliot J Rayfield
Cardiovascular Diabetology , 2002, DOI: 10.1186/1475-2840-1-1
Abstract: Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease [1-3]. Atherosclerosis accounts for virtually 80% of all deaths among North American diabetic patients, compared with one third of all deaths in the general North American population [1]. More then 75% of all hospitalizations for diabetic complications are attributable to cardiovascular disease.Prolonged exposure to hyperglycemia is now recognized as the primary casual factor in the pathogenesis of diabetic complications [4-6]. Hyperglycemia induces a large number of alterations in vascular tissue that potentially promote accelerated atherosclerosis. Currently, three major mechanisms have emerged that encompass most of the pathological alterations observed in the vasculature of diabetic animals and humans: 1) Nonenzymatic glycosylation of proteins and lipids 2) oxidative stress 3) protein kinase C (PKC) activation. Importantly, these mechanisms are not independent. For example, hyperglycemia-induced oxidative stress promotes the formation of advanced glycosylation end products and PKC activation [7].The effects of hyperglycemia are often irreversible and lead to progressive cell dysfunction [8]. For example, in diabetic patients with functioning pancreatic transplants renal pathology continues to progress for at least 5 years after diabetes has been cured [8]. The mechanism for these observations is unclear, but suggests that cellular perturbations may persist despite the return of normoglycemia (the so-called memory effect). Thus, persistent rather than transient, acute metabolic changes are of pivotal importance in the pathogenesis of diabetic complications.One of the important mechanisms responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in arterial walls, collectively known as Maillard, or browning reaction [9]. Glucose forms chemica
Graphical Modeling of Gene Expression in Monocytes Suggests Molecular Mechanisms Explaining Increased Atherosclerosis in Smokers  [PDF]
Ricardo A. Verdugo, Tanja Zeller, Maxime Rotival, Philipp S. Wild, Thomas Münzel, Karl J. Lackner, Henri Weidmann, Ewa Ninio, David-Alexandre Trégou?t, Fran?ois Cambien, Stefan Blankenberg, Laurence Tiret
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0050888
Abstract: Smoking is a risk factor for atherosclerosis with reported widespread effects on gene expression in circulating blood cells. We hypothesized that a molecular signature mediating the relation between smoking and atherosclerosis may be found in the transcriptome of circulating monocytes. Genome-wide expression profiles and counts of atherosclerotic plaques in carotid arteries were collected in 248 smokers and 688 non-smokers from the general population. Patterns of co-expressed genes were identified by Independent Component Analysis (ICA) and network structure of the pattern-specific gene modules was inferred by the PC-algorithm. A likelihood-based causality test was implemented to select patterns that fit models containing a path “smoking→gene expression→plaques”. Robustness of the causal inference was assessed by bootstrapping. At a FDR ≤0.10, 3,368 genes were associated to smoking or plaques, of which 93% were associated to smoking only. SASH1 showed the strongest association to smoking and PPARG the strongest association to plaques. Twenty-nine gene patterns were identified by ICA. Modules containing SASH1 and PPARG did not show evidence for the “smoking→gene expression→plaques” causality model. Conversely, three modules had good support for causal effects and exhibited a network topology consistent with gene expression mediating the relation between smoking and plaques. The network with the strongest support for causal effects was connected to plaques through SLC39A8, a gene with known association to HDL-cholesterol and cellular uptake of cadmium from tobacco, while smoking was directly connected to GAS6, a gene reported to have anti-inflammatory effects in atherosclerosis and to be up-regulated in the placenta of women smoking during pregnancy. Our analysis of the transcriptome of monocytes recovered genes relevant for association to smoking and atherosclerosis, and connected genes that before, were only studied in separate contexts. Inspection of correlation structure revealed candidates that would be missed by expression-phenotype association analysis alone.
Molecular Imaging of Atherosclerosis  [cached]
Danny L Costantini
University of Toronto Medical Journal , 2010, DOI: 10.5015/utmj.v87i2.1172
Abstract: Molecular imaging is a rapidly evolving field that aims to develop novel technologies and methods to image specific biological processes in the living organism at the cellular and molecular level. This review discusses several novel imaging strategies that exploit the unique biological properties of atherosclerosis to detect key aspects of the disease. Among the approaches, targeting macrophage activity, protease activity, apoptosis and angiogenesis for in vivo molecular imaging of atherosclerosis have demonstrated the greatest potential for translation into the clinical setting.
Molecular MRI of Atherosclerosis  [PDF]
Alkystis Phinikaridou,Marcelo E. Andia,Sara Lacerda,Silvia Lorrio,Marcus R. Makowski,René M. Botnar
Molecules , 2013, DOI: 10.3390/molecules181114042
Abstract: Despite advances in prevention, risk assessment and treatment, coronary artery disease (CAD) remains the leading cause of morbidity and mortality in Western countries. The lion’s share is due to acute coronary syndromes (ACS), which are predominantly triggered by plaque rupture or erosion and subsequent coronary thrombosis. As the majority of vulnerable plaques does not cause a significant stenosis, due to expansive remodeling, and are rather defined by their composition and biological activity, detection of vulnerable plaques with x-ray angiography has shown little success. Non-invasive vulnerable plaque detection by identifying biological features that have been associated with plaque progression, destabilization and rupture may therefore be more appropriate and may allow earlier detection, more aggressive treatment and monitoring of treatment response. MR molecular imaging with target specific molecular probes has shown great promise for the noninvasive in vivo visualization of biological processes at the molecular and cellular level in animals and humans. Compared to other imaging modalities; MRI can provide excellent spatial resolution; high soft tissue contrast and has the ability to simultaneously image anatomy; function as well as biological tissue composition and activity.
Wine, alcohol and atherosclerosis: clinical evidences and mechanisms
Luz, P.L. da;Coimbra, S.R.;
Brazilian Journal of Medical and Biological Research , 2004, DOI: 10.1590/S0100-879X2004000900001
Abstract: atherosclerosis is a chronic inflammatory disease which may cause obstructions of the coronary, cerebral and peripheral arteries. it is typically multifactorial, most often dependent on risk factors such as hypercholesterolemia, diabetes, smoking, hypertension, sedentarism, and obesity. it is the single main cause of death in most developed countries due to myocardial infarction, angina, sudden death, and heart failure. several epidemiological studies suggest that moderate alcohol intake, especially red wine, decrease cardiac mortality due to atherosclerosis. the alcohol effect is described by a j curve, suggesting that moderate drinkers may benefit while abstainers and heavy drinkers are at higher risk. experimental studies indicate that most beneficial effects of drinking are attributable to flavonoids that are present in red wine, purple grape juice and several fruits and vegetables. the mechanisms include antiplatelet actions, increases in high-density lipoprotein, antioxidation, reduced endothelin-1 production, and increased endothelial nitric oxide synthase expression which causes augmented nitric oxide production by endothelial cells. these findings lead to the concept that moderate red wine drinking, in the absence of contraindications, may be beneficial to patients who are at risk of atherosclerotic cardiovascular events. moreover, a diet based on fruits and vegetables containing flavonoids may be even more beneficial.
Wine, alcohol and atherosclerosis: clinical evidences and mechanisms  [cached]
Luz P.L. da,Coimbra S.R.
Brazilian Journal of Medical and Biological Research , 2004,
Abstract: Atherosclerosis is a chronic inflammatory disease which may cause obstructions of the coronary, cerebral and peripheral arteries. It is typically multifactorial, most often dependent on risk factors such as hypercholesterolemia, diabetes, smoking, hypertension, sedentarism, and obesity. It is the single main cause of death in most developed countries due to myocardial infarction, angina, sudden death, and heart failure. Several epidemiological studies suggest that moderate alcohol intake, especially red wine, decrease cardiac mortality due to atherosclerosis. The alcohol effect is described by a J curve, suggesting that moderate drinkers may benefit while abstainers and heavy drinkers are at higher risk. Experimental studies indicate that most beneficial effects of drinking are attributable to flavonoids that are present in red wine, purple grape juice and several fruits and vegetables. The mechanisms include antiplatelet actions, increases in high-density lipoprotein, antioxidation, reduced endothelin-1 production, and increased endothelial nitric oxide synthase expression which causes augmented nitric oxide production by endothelial cells. These findings lead to the concept that moderate red wine drinking, in the absence of contraindications, may be beneficial to patients who are at risk of atherosclerotic cardiovascular events. Moreover, a diet based on fruits and vegetables containing flavonoids may be even more beneficial.
Immune Mechanisms in Atherosclerosis, Especially in Diabetes Type 2  [PDF]
Johan Frosteg?rd
Frontiers in Endocrinology , 2013, DOI: 10.3389/fendo.2013.00162
Abstract: Atherosclerosis and ensuing cardiovascular disease (CVD) are major complications of diabetes type 2. Atherosclerosis is a chronic inflammatory condition involving immunocompetent cells of different types present in the lesions. Even though inflammation and immune activation may be more pronounced in atherosclerosis in diabetes type 2, there does not appear to be any major differences between diabetics and non-diabetics. Similar factors are thus implicated in atherosclerosis-associated immune activation in both groups. The cause of immune activation is not known and different mutually non-exclusive possibilities exist. Oxidized and/or enzymatically modified forms of low-density lipoprotein (OxLDL) and dead cells are present in atherosclerotic plaques. OxLDL could play a role, being pro-inflammatory and immunostimulatory as it activates T-cells and is cytotoxic at higher concentrations. Inflammatory phospholipids in OxLDL are implicated, with phosphorylcholine (PC) as one of the exposed antigens. Antibodies against PC (anti-PC) are anti-atherogenic in mouse studies, and anti-PC is negatively associated with development of atherosclerosis and CVD in humans. Bacteria and virus have been discussed as potential causes of immune activation, but it has been difficult to find direct evidence supporting this hypothesis, and antibiotic trials in humans have been negative or inconclusive. Heat shock proteins (HSP) could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include cytokines such as interleukin 1β (IL-1β), tumor necrosis factor (TNF), and also lipid mediators as leukotrienes. In addition, in diabetes, hyperglycemia and oxidative stress appear to accelerate the development of atherosclerosis, one mechanism could be via promotion of immune reactions. To prove that immune reactions are causative of atherosclerosis and CVD, further studies with immune-modulatory treatments are needed.
Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins  [PDF]
Graziamaria Corbi,Andrea Bianco,Viviana Turchiarelli,Michele Cellurale,Federica Fatica,Aurora Daniele,Gennaro Mazzarella,Nicola Ferrara
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140612696
Abstract: The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD +-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems.
Statins and myopathy: molecular mechanisms  [cached]
O.M. Drapkina,E.M. Chernova,O.N. Korneeva
Rational Pharmacotherapy in Cardiology , 2012,
Abstract: The safety of statin therapy is considered. In particular the reasons of a complication such as myopathy are discussed in detail. The molecular mechanisms of statin myopathy, as well as its risk factors are presented. The role of coenzyme Q10 in the myopathy development and coenzyme Q10 application for the prevention of this complication are considered.
Molecular action mechanisms of the immunomodulators
Belteghi, C.
Medicamentul Veterinar , 2008,
Abstract: The special attention paid, during the last period, to researches on immunomodulators and on the possibilities of the immune response unspecific manipulation represent an answer to the more and more stringent needs of finding out complementary and/or alternative solutions to the classic therapeutic methods. With this work, we intended to present synthetically the progress recorded in the field of molecular mechanisms that represent the base for the effects exerted by various categories of immunomodulator products. The imunomodulator mechanisms performed through Toll-like receptors, receptors for cytokines, receptors for hormones and through calcineurin have been described in this paper work.
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