Course Of Atherosclerosis Research Articles

Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation

Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion.

Athero-protective actions of two oral antidiabetic drugs: Suppression of inflammation and oxidative stress

Diabetes mellitus increases the risk and accelerates the clinical course of atherosclerosis, and is responsible for majority of the deaths and disabilities in type 2 diabetic population. [1] Optimal strategies to prevent the onset or progression of atherosclerosis will improve the clinical outcome of this high-risk population. In the current study, the research team showed that two antidiabetic agents, namely Glimepiride and Repaglinide, prevent the progression of atherosclerosis in high fat diet fed rabbits, by exerting their anti-inflammatory and anti-oxidate effects.Read more....,

Immune Modulation of Atherosclerosis

The notion that inflammation plays a role in atherosclerosis dates to separate observations by Virchow and von Rokitansky in the middle of the 19 th century that atherosclerotic blood vessels contained evidence of cellular inflammation. This concept remained stagnant until the 1970s, when Russell Ross demonstrated that monocyte adhesion to the endothelial surface was an early and essential feature of atherosclerosis.1 These observations, coupled with knowledge that modified low-density lipoprotein (LDL) supports foam cell formation and promotes atherosclerosis disease activity,2 focused early investigative efforts on monocytes and macrophages, the foam cell precursors. Indeed, it is clear that neutrophils3 and monocytes enter lesion-prone arterial sites, the latter differentiate into macrophages, and then take up accumulated LDL-cholesterol to form foam cells and early atherosclerotic lesions. Innate immune responses, such as recognition of modified LDL-derived epitopes via macrophage Toll-like receptors, prompts cytokine-mediated recruitment of other inflammatory cells to the lesion4 that, in turn, promote the adaptive immune responses responsible for the chronic inflammation of atherosclerosis. Emerging evidence has helped to refine this paradigm and identify critical events in adaptive immunity that could represent therapeutic opportunities for immune modulation of atherosclerosis. Activated endothelium is characterized by adhesion molecule expression and reduced barrier function that mediate the recruitment of both monocytes5 and T-cells into lesion-prone sites in the arterial wall. With regard to T-cells, histological examination of atherosclerotic lesions demonstrate the presence of both CD4+ T helper (Th) cells, CD8+ cytotoxic T (Tc) cells, and regulatory T cells (Treg) in lesions, although Th cells generally predominate. Lesional T-cells represent a cellular minority …

Lipid Management for the Prevention of Cardiovascular Disease

Lowering low density lipoprotein (LDL) - cholesterol is one of the key issues in modern preventive cardiology by which we are able to interact with the natural course of atherosclerosis. Diet and healthy life style are mandatory for the treatment of CAD high risk patients. Numerous lipid lowering trials confirmed the beneficial effect of statins in primary as well as secondary prevention. By this statins are the basic treatment in patients with coronary artery disease (CAD) or diabetes mellitus or both. In order to reach LDL - cholesterol target levels (LDL - cholesterol < 100 mg/dl) in patients with CAD the use of potent statins or a lipid lowering combination therapy might be necessary. In our days we are able to lower LDL-cholesterol by more than 50% with drug treatment, which should enable us to reach the optimal LDL-cholesterol level in most patients.

Unsaturated FAs prevent palmitate-induced LOX-1 induction via inhibition of ER stress in macrophages

Palmitic acid (PA) upregulates oxidized LDL receptor-1 (LOX-1), a scavenger receptor responsible for uptake of oxidized LDL (oxLDL), and enhances oxLDL uptake in macrophages. However, the precise underlying mechanism remains to be elucidated. PA is known to induce endoplasmic reticulum (ER) stress in various cell types. Therefore, we investigated whether ER stress is involved in PA-induced LOX-1 upregulation. PA induced ER stress, as determined by phosphorylation of PERK, eIF2α, and JNK, as well as induction of CHOP in macrophage-like THP-1 cells. Inhibitors [4-phenylbutyric acid (PBA), sodium tauroursodeoxycholate (TUDCA), and salubrinal] and small interfering RNA (siRNA) for the ER stress response decreased PA-induced LOX-1 upregulation. Thapsigargin, an ER stress inducer, upregulated LOX-1, which was decreased by PBA and TUDCA. We next examined whether unsaturated FAs could counteract the effect of PA. Both oleic acid (OA) and linoleic acid (LA) suppressed PA-induced LOX-1. Activation of the ER stress response observed in the PA-treated cells was markedly attenuated when the cells were cotreated with OA or LA. In addition, OA and LA suppressed thapsigargin-induced LOX-1 upregulation with reduced activation of ER stress markers. Our results indicate that activation of ER stress is involved in PA-induced LOX-1 upregulation in macrophages, and that OA and LA inhibit LOX-1 induction through suppression of ER stress.

Protective role of parnaparin in reducing systemic inflammation and atherosclerotic plaque formation in ApoE-/- mice

Atherosclerosis is a degenerative disease whose role in the onset and development of cardiovascular pathologies and complications is of importance. Due to its silent but progressive development, and considering the endothelial, immunological and inflammatory processes that are involved in its clinical course, this still relatively unknown pathological condition has been and continues to be a matter of investigation worldwide. Our experience with previous studies on atherosclerosis led us to investigate the possible influence of a low molecular weight heparin (LMWH) - Parnaparin® on the development and clinical course of atherosclerosis in double knock-out laboratory animals (ApoE-/- mice). Our experiments demonstrated a possible role of Parnaparin (PNP) in the control of atherogenic disease. In fact, in treated mice vs. untreated ones, PNP reduced the number and the size of atherosclerotic lesions in the aortic wall, as well as the development of liver steatosis, which was massive in untreated animals and moderate in treated ones. These preliminary observations require further clinical studies, but demonstrate a possible role of Parnaparin in the control of the development and clinical evolution of atherosclerosis and liver steatosis in laboratory animals.

Inflammation, Adiponectin, Obesity and Cardiovascular Risk

The development of atherosclerotic lesions leading to myocardial infarction (MI) or stroke encompasses a cascade of cellular and molecular events that can well be characterized as a chronic immune-mediated inflammation occurring preferentially in the biologic surrounding of the so called metabolic syndrome. Adipokines, chemokines, cytokines, and their receptors are critically involved in the initiation and perpetuation of atherosclerosis, and they play important roles at all levels in the pathogenesis of this disease. Metabolic risk profiles associated with sedentary lifestyle, obesity, especially intra-abdominal fat accumulation, insulin resistance, and dyslipidemia pave the way for a chronic, immune-mediated vascular inflammation around vascular lipid deposits. In the present article, the impact of adiponectin, monocyte and T-cell associated cytokines (with emphasis on Neopterin), individual adipose tissue - distribution and pleiotropic drug effects on the individual course of atherosclerosis and associated cardiovascular disease are reviewed.

Surgical or Interventional Revascularization in Diabetic Patients with Coronary Artery Disease?

The combination of diabetes mellitus and coronary artery disease (CAD) constitutes an aggressive disease characterized biologically by chronic inflammatory, proliferative and pro-thrombotic situation. In the "diabetic patient" the increased frequency and gravity of simultaneous myocardial infarction and the deterioration of congestive heart failure contribute to the inevitable unfavourable final result. Diabetes accelerates the natural course of atherosclerosis and involves a great number of coronary vessels with more diffuse atherosclerotic lesions. Moreover, the risks of plaque ulceration and thrombosis have been shown to be considerably higher in diabetic patients. The treatment should be also aggressive and be based on the combined treatment of CAD and the effective regulation of glucose levels. The decision of revascularization in the diabetic patient should be posed relatively earlier. The surgical choice of revascularization seems to be advantageous over the interventional, with better early and late results.

Editorial: Inflammation, Thrombosis and Vascular Biology: Translating Ideas into Cardiovascular Research and Therapy

Advances in basic and clinical sciences over the past decades have substantially improved our understanding of inflammatory and thrombotic pathways implicated in atherogenesis. It is now clear that multiple genetic and environmental factors interfere with the natural course of atherosclerosis in early life and lead toward premature clinical manifestations in the adolescence and in the middle age. Importantly, various molecular and cellular agents with pro-atherogenic properties have been identified, and similarities have been found between atherosclerotic vascular disease, chronic inflammatory disorders and cancer [1, 2], all of which can be viewed as diseases of premature aging. Identification of common pathways of aging, and premature morbidity and mortality in these disorders has prompted the search for therapeutic means with universal beneficial effects. In fact, over the past decade, we have witnessed a strong emphasis on anti-inflammatory effects of cardiovascular drugs, such as angiotensin converting enzyme inhibitors (ACE-I), statins, aspirin, which are believed to reduce incidence of vascular events by acting not only on their primary therapeutic targets but also on the inflammatory process [3].

Host cholesterol and inflammation as common key regulators of toxoplasmosis and artherosclerosis development

Atherosclerosis and toxoplasmosis are two widely prevalent diseases worldwide. The relationship between these diseases is now being elucidated. Atherosclerosis is a disease with three main components: increased blood lipoprotein/cholesterol and their deposition in the arterial wall, an important Th1-mediated proinflammatory reaction and thrombogenic status. Toxoplasma gondii, in turn, is dependent on host cholesterol for optimal intracellular growth and replication. As a result, host cholesterol will be cleared from the blood, reducing plasma low-density lipoprotein, a crucial atherosclerosis risk factor. On the other hand, T. gondii infection elicits an important Th1 systemic inflammatory response in the host. Therefore, this additional proinflammatory stimulus may impose an enhanced pro-atherogenic environment in the host. As result, the association between these two diseases in one individual could change the course of atherosclerosis. In this review, we demonstrate that the host–parasite relationship is complex and that the outcome of each disease is dependent on the availability of intracellular cholesterol, as well as the intensity of the inflammatory reaction triggered by the parasite. We also discuss the possible clinical implications of these studies.

The Use of Carotid Artery Ultrasonography in Different Clinical Conditions

B-mode ultrasonography of the carotid artery is a non-invasive, informative and reproducible technique used for the assessment of prevalence and course of atherosclerosis in a variety of clinical conditions. Visualization of intima-media complex, atherosclerotic plaques, rough arterial wall and calcifications of the carotid artery may be useful for the assessment of atherosclerotic burden. The latter was confirmed in a recent consensus statement of the American Society of Echocardiography. Detection of structural changes, such as Menkeber’s sclerosis of the medial layer of the carotid artery, carotid aneurysm may indicate advanced vascular pathology and prompt an appropriate treatment. Ultrasound images of patients with atherosclerotic plaque and Menkeberg’s sclerosis are presented and issues related to clinical significance of the common carotid artery intima-media thickness are discussed.

Insights Into the Role of Infection in Atherogenesis and in Plaque Rupture

The potential contribution of infection to the induction and progression of atherosclerosis has been characterized by profound controversy, continuing to the present time. Controversy also surrounds the concept that infection can precipitate plaque rupture, an event complicating the course of atherosclerosis and clinically characterized by acute myocardial infarction and death. The purpose of this article is (1) to review what we believe are the most compelling data that either are compatible with or refute the concept that infection plays a role in atherogenesis or plaque rupture; (2) to present the mechanisms that may contribute to such effects; and (3) to discuss the impact on the infection/atherosclerosis paradigm of the recent negative therapeutic trials examining the effects of macrolide antibiotics on cardiovascular end points in patients with coronary artery disease (CAD). Although anecdotal information existed for many years suggesting that acute infection can trigger an acute myocardial infarction,1,2 it was the groundbreaking work by Minick and Fabricant and their coworkers3,4 in the1970s that began the serious scientific exploration of the relation between infection and atherosclerosis. These investigators demonstrated that Marek’s disease virus, an avian herpesvirus, caused atherosclerotic-like lesions in multiple arteries of chickens and that infection of smooth muscle cells (SMCs) with the virus in vitro caused cholesterol accumulation. Evidence was subsequently published extending the infection/atherosclerosis paradigm to humans. Thus, pathogens were found to reside in human atherosclerotic vessels,5–8 and seroepidemiological studies demonstrated an association between pathogen-specific antibodies and atherosclerosis. Such associations were found with multiple pathogens, including cytomegalovirus (CMV), herpes simplex virus (HSV) types 1 and 2, Chlamydia pneumonia , Helicobacter pylori , and hepatitis A virus, as well as periodontal pathogens.9–16 However, other studies failed to show such associations,17,18 leading to discussions of the limitations of seroepidemiological studies in evaluating a causal role between …

Noninvasive assessment of endothelial function and ST segment changes during exercise testing in coronary artery disease

Endothelial function (EF) plays an important role in the onset and clinical course of atherosclerosis, although its relationship with the presence and extent of coronary artery disease (CAD) has not been well defined. We evaluated EF and the ST segment response to an exercise test in patients with a broad spectrum of CAD defined by coronary angiography. Sixty-two patients submitted to diagnostic catheterization for the evaluation of chest pain or ischemia in a provocative test were divided into three groups according to the presence and severity of atherosclerotic lesions (AL): group 1: normal coronaries (N = 19); group 2: CAD with AL <70% (N = 17); group 3: CAD with AL > or = 70% (N = 26). EF was evaluated by the percentage of flow-mediated dilatation (%FMD) in the brachial artery during reactive hyperemia induced by occlusion of the forearm with a pneumatic cuff for 5 min. Fifty-four patients were subjected to an exercise test. Gender and age were not significantly correlated with %FMD. EF was markedly reduced in both groups with CAD (76.5 and 73.1% vs 31.6% in group 1) and a higher frequency of ischemic alterations in the ST segment (70.8%) was observed in the group with obstructive CAD with AL > or = 70% during the exercise test. Endothelial dysfunction was observed in patients with CAD, irrespective of the severity of injury. A significantly higher frequency of ischemic alterations in the ST segment was observed in the group with obstructive CAD. EF and exercise ECG differed among the three groups and may provide complementary information for the assessment of CAD.

Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases

Oxidized LDL (oxLDL) increase in patients affected by type-2 diabetes, obesity, and metabolic syndrome. Likewise, insulin resistance, an impaired responsiveness of target tissues to insulin, is associated with those pathological conditions. To investigate a possible causal relationship between oxLDL and the onset of insulin resistance, we evaluated the response to insulin of 3T3-L1 adipocytes treated with oxLDL. We observed that oxLDL inhibited glucose uptake (-40%) through reduced glucose transporter 4 (GLUT4) recruitment to the plasma membrane (-70%), without affecting GLUT4 gene expression. These findings were associated to the impairment of insulin signaling. Specifically, in oxLDL-treated cells insulin receptor (IR) substrate-1 (IRS-1) was highly degraded likely because of the enhanced Ser(307)phosphorylation. This process was largely mediated by the activation of the inhibitor of kappaB-kinase beta (IKKbeta) and the c-Jun NH(2)-terminal kinase (JNK). Moreover, the activation of IKKbeta positively regulated the nuclear content of nuclear factor kappaB (NF-kappaB), by inactivating the inhibitor of NF-kappaB (IkappaBalpha). The activated NF-kappaB further impaired per se GLUT4 functionality. Specific inhibitors of IKKbeta, JNK, and NF-kappaB restored insulin sensitivity in adipocytes treated with oxLDL. These data provide the first evidence that oxLDL, by activating serine/threonine kinases, impaired adipocyte response to insulin affecting pathways involved in the recruitment of GLUT4 to plasma membranes (PM). This suggests that oxLDL might participate in the development of insulin resistance.

Utility of Aspirin Therapy in Patients With the Cardiometabolic Syndrome and Diabetes

Paralleling the rise in obesity, the cardiometabolic syndrome is a rapidly growing health problem in the United States. There is a 3-fold increase in the prevalence of coronary heart disease, myocardial infarction, and stroke due to the coagulation, hemodynamic, and metabolic abnormalities seen in these individuals. The use of aspirin for secondary prevention and, to a lesser degree, primary prevention of cardiovascular events is a well-established standard of care. However, in patients with diabetes or the cardiometabolic syndrome, the role of aspirin in prevention of cardiovascular events remains controversial. In this review, the authors examine the clinical trial data on the use of aspirin in diabetes and the cardiometabolic syndrome for cardiovascular protection. They also explore, in addition to aspirin's effects on platelet aggregation, some of the mechanisms by which aspirin may favorably alter the course of atherosclerosis, effects on endothelial function, and glycemia.

TGF-beta signaling in atherosclerosis and restenosis

Current theories suggest that atherosclerotic and restenotic lesions result from imbalances between systems that are proinflammatory/fibroproliferative versus the endogenous inhibitory systems that normally limit inflammation and vascular wound repair. Abnormalities in one of the major regulatory pathways, the transforming growth factor-beta (TGF-beta) system, has been characterized in both animal models and in human lesions and lesion-derived cells. TGF-beta signaling is capable of regulating many of the key aspects of atherosclerosis and restenosis: inflammation, chemotaxis, fibrosis, proliferation, and apoptosis. There are significant decreases in TGF-beta activity in patients with atherosclerosis, and equally important changes in the way cells respond to TGF-beta during atherogenesis. Evidence from multiple sources indicates that experimental modulation of TGF-beta activity, or TGF-beta responses, changes the course of atherosclerosis and intimal hyperplasia. Cells derived from human lesions produce adequate TGF-beta levels, but are resistant to the antiproliferative and apoptotic effects of TGF-beta. An evolving theory describes TGF-beta as a major orchestrator of the vascular repair process, with observable defects in its production, activation, and cellular responses during the atherosclerotic and restenotic processes.

Secondary prevention of atherothrombotic events after ischemic stroke.

Atherosclerotic vascular disease is the leading cause of ischemic stroke, resulting in occlusive or severely stenotic lesions of major intracranial or extracranial arteries and narrowing of small penetrating arteries of the brain. Atherosclerosis of the coronary arteries (ie, coronary artery disease) is an indirect cause of cardioembolic stroke secondary to myocardial infarction. Ischemic heart disease may also be complicated by atrial fibrillation and cardioembolic stroke. Prevention of recurrent stroke and other ischemic events, including myocardial infarction, is a key component of treatment for patients with symptomatic ischemic cerebrovascular disease. Prevention of recurrent stroke involves controlling those factors that promote the course of atherosclerosis, including hypertension, hyperlipidemia, diabetes mellitus, and smoking, as well as such local interventions as carotid endarterectomy and endovascular treatment. Nevertheless, administration of antiplatelet agents remains the core of management for preventing recurrent stroke and other cardiovascular events in at-risk patients.

TGF-beta signaling in atherosclerosis and restenosis

Current theories suggest that atherosclerotic and restenotic lesions result from imbalances between systems that are proinflammatory/fibroproliferative versus the endogenous inhibitory systems that normally limit inflammation and vascular wound repair. Abnormalities in one of the major regulatory pathways, the transforming growth factor-&szlig; (TGF-&szlig;) system, has been characterized in both animal models and in human lesions and lesion-derived cells. TGF-&szlig; signaling is capable of regulating many of the key aspects of atherosclerosis and restenosis: inflammation, chemotaxis, fibrosis, proliferation, and apoptosis. There are significant decreases in TGF-&szlig; activity in patients with atherosclerosis, and equally important changes in the way cells respond to TGF-&szlig; during atherogenesis. Evidence from multiple sources indicates that experimental modulation of TGF-&szlig; activity, or TGF-&szlig; responses, changes the course of atherosclerosis and intimal hyperplasia. Cells derived from human lesions produce adequate TGF-&szlig; levels, but are resistant to the antiproliferative and apoptotic effects of TGF-&szlig;. An evolving theory describes TGF-&szlig; as a major orchestrator of the vascular repair process, with observable defects in its production, activation, and cellular responses during the atherosclerotic and restenotic processes.

Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition on serum matrix metalloproteinase-13 and tissue inhibitor matrix metalloproteinase-1 levels as a sign of plaque stabilization

Atherosclerotic plaques are composed of a lipid rich core, which is covered by a collagen rich fibrous cap. Rupture of the atherosclerotic plaque with superimposed thrombosis is the main cause of acute coronary syndromes, including acute myocardial infarction and unstable angina. The stability of the plaque depends on its collagen content; degradation of the collagen leads to a vulnerable plaque that is prone to rupture. Recent studies have demonstrated a critical role for matrix metalloproteinases (MMPs) in the degradation of the collagen content and the reduction of mechanical stability of the atherosclerotic plaques. Increased expression of various MMPs has been shown in the tissue sections of atherosclerotic plaques. The increased expression of MMPs in the atheroma also leads to increased MMP levels in the circulation. The cholesterol lowering drugs - 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) - decrease the tissue expression of various MMPs in atheromatous plaques by attenuating the inflammatory process that promotes MMP expression during the course of atherosclerosis. However, the effect of statin treatment on the serum levels of MMP-13, which has a critical role in the initiation of collagen degradation, is unknown. On the basis of these previous studies, we discuss the need for studies on the effect of statin treatment on the serum levels of MMP-13 and tissue inhibitor of matrix metalloproteinase (TIMP-1) levels in hypercholesterolemic patients.

Endothelium and nitric oxide

Studied nature of the "blood vessels relaxing factor" derived from endothelium that was identified as nitric oxide caused intensive scientific research on nitric oxide regarding some aspects of its impact on human physiological and pathological processes. The objective of this short review is to discuss widely used (in the clinical practice) direct and indirect donors of nitric oxide and/or other agents, increasing nitric oxide concentration in human body, and their beneficial role for the prevention of atherosclerosis. Under physiological conditions, endothelium regulates the tone of blood vessels, homeostasis of which is maintained by endothelium-generated vasoconstrictors and vasodilators. The most important vasodilator and the main substance produced by the endothelium is nitric oxide. The failure of synthesis and/or the lost of nitric oxide bioavailability is the major feature of endothelial dysfunction and key factor initiating progression of atherosclerosis. The endothelial dysfunction initiates the series of events, which stimulate and aggravate the course of atherosclerosis by increasing endothelial permeability, platelet aggregation, and leukocyte adhesion, and cytokine expression. Further, the review deals with the mechanisms of action of statins, angiotensin-converting enzyme inhibitors, L-arginine, direct nitric oxide donors (nitroglycerin, isosorbide mononitrate and isosorbide dinitrate), and indirect nitric oxide donors (phosphodiesterase-V inhibitors, K(ATP) openers).