Institute For Cardiovascular Research Vu Icar Vu

Netherlands

Institute For Cardiovascular Research Vu Icar Vu

Netherlands
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Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Angiogenesis is the outgrowth of new blood vessels from existing ones. It occurs during development, but stops normally at maturity. In the healthy adult it is only found in the endometrium and ovaries during the menstrual cycle, and in conditions associated with tissue repair, such as wound and fracture healing and in bone remodeling. Furthermore, angiogenesis is induced in a number of diseases including cancer, rheumatoid arthritis and diabetic retinopathy. Anti-angiogenic therapy has been proposed as an additional treatment of tumors. Because such treatment will be long-lasting, non-selective suppression of angiogenesis may interfere with proper healing of minor and major tissue injuries. The overall aim of the program is to provide insight into the regulation of the cellular processes involved in angiogenesis, in order to recognize key factors involved in and discriminating between tumor angiogenesis and wound and bone healing and to provide a rationale for selective inhibition of tumor angiogenesis. The program focuses on the role of cell-matrix interactions and proteases in angiogenesis and cell invasion. The programme make use of angiogenesis models and gene analysis techniques. Models of human and mouse angiogenesis in vitro and in vivo (bone, wounds with fibrinous exudates) and angiogenesis of human tumors in nude mice have been developed, and their quantification has been validated. Studies on endothelial cell activation and signal transduction, analysis of angiogenesis-related gene expression, construction of hybrid and mutant proteins, and expression after transfection with adenoviral vectors are presently done on a routine basis in our groups. The experimental approach of the program involves the following aspects: I. Analysis of gene expression in various forms and stages of angiogenesis will be performed by microarray assay to establish differences in gene expression (patterns) in various forms and stages of angiogenesis, and to identify pathways or gene products that can be used for selective inhibition of specific forms of angiogenesis. II. Three groups of angiogenesis inhibitors that are related to the interaction of the endothelial cell with its environment are evaluated regarding their ability to inhibit various types of angiogenesis. (1) General and selective inhibitors of proteases involved in the migration and invasion of endothelial cells. (2) Inhibitors of cell-matrix interaction. (3) Endogenous endothelium-specific inhibitors derived from local proteolysis. These inhibitors are tested in models of various types of angiogenesis to establish whether a specific pattern of inhibition exists and to identify the general mechanisms by which they act. Targets for inhibition will also be selected on the basis of the gene products found by the microarray analysis. III. Changes in gene expression during inhibition of angiogenesis will be monitored by microarray assay in selected in vitro angiogenesis models to verify the pattern of inhibition that is assumed/expected to occur by angiogenesis inhibitors. Subsequently, we will evaluate the mode of action of other and new inhibitors with an unknown mode of action. IV. The recognition of specific activities involved in specific types of stages of angiogenesis provides a means to generate new specific inhibitors based on mutants and hybrid proteins that have a selective inhibitory effect on angiogenesis. These proteins will be expressed and tested in the appropriate models directly or after adenoviral transfer of their cDNA. The program is conducted in collaboration with TNO-PG (Gaubius Laboratory, Division of Vascular Research) and the Leiden University Medical Centre LUMC (Department of Endocrinology).


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

This project aims at improving the circulation in ischemic tissues by gene transfer of VEGF and related factors. The first part of the project deals with mouse studies in which ischemia is induced in the leg and viral vectors containing VEGF and other factors are attributed to the ischemic area. Visualization and quantification of the formation of collateral vessels and evaluation of increased blood flow are the first objectives. Subsequently, the way of application and involvement of different cell types is evaluated. Clinical studies are prepared. The studies are done at TNO Prevention and Health (TNO-PG) and Leiden University Medical Centre (LUMC) in the context of the tripartite angiogenesis program of VUMC - LUMC -TNO-PG.


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

None


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Background: On the basis of current knowledge, anti-coagulation in patients with left ventricular dysfunction (LVD) and sinus rhythm seems to be of potential value in order to prevent cardiovascular events; however no randomized, prospective data are available to support this. In the SAVE-trial every 5% decrease in ejection fraction was associated with an 18% increase in risk of stroke. In the SOLVD trial, sudden cardiac death was significantly reduced by 32% in patients with anti-coagulation and 24 percent with antiplatelet agents, though not randomized and not retrospectively evaluated. Furthermore, a significant reduction in all-cause mortality and reduction of hospitalization for heart failure was observed in patients treated with anti-coagulation. However, this benefit associated with coumarin therapy must also be evaluated in relation to the risk of bleeding. Hypothesis: Coumarin and aspirin will be non-inferior to aspirin alone in reducing cardiovascular events defined as a combined endpoint including all-cause mortality, myocardial infarction, cardiovascular revascularization or hospitalization, heart transplantation, stroke and other systemic embolic events during 1-year follow-up in patients with severe LVD, as assessed by 2D-echo, and sinus rhythm. Objectives: (1) To compare the 1-year clinical efficacy (= the predefined combined end-point) of coumarin and aspirin versus aspirin in patients with severe (a)symptomatic LVD by 2D-echo. (2) To evaluate flow patterns within the two groups and relate normal and abnormal left ventricular flow with predefined combined endpoint and formation of left ventricular thrombus. (3) To compare safety with respect to minor and major bleeding events, need for blood cell or platelet transfusion, spontaneously reported clinical adverse esperiences. (4) Also, costs associated with (repeated) echo examination, drug therapy and hospitalizations due to cardiovascular events will be assessed. Methods: Candidates are postinfarct patients selected from the echolabs with an ejection fraction less than 40% not already on coumarin therapy and without a left ventricular thrombus or aneurysm. Patients can be included regardless symptomatology, thus asympomatic patients are also candidates. Patients with LVD and an ejection fraction >40% will be followed as a control group for evaluation of flow patterns and its relevance to thrombus formation and combined clinical endpoints. This multicenter study will include approximately 1000 patients and may demonstrate the value of anti-coagulation in patients with severe LVD.


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Recent data suggest that glucose-insuline-potassium infusion (GIK) in acute myocardial infarction results in an improved survival of patients, especially in patients undergoing reperfusion therapy. The mechanisms of improved survival by GIK infusion are not well defined but experimental data suggest that several mechanisms may play a role that limit infarct size. We have recently discovered by chance that GIK infusion in patients with an acute myocardial infarction resulted in improvement of regional and global left ventricular function. Furthermore, we found that only the non-contractile but viable segments in the infarct area showed improvement during GIK infusion. These data support the notion that GIK may reduce infarct size if reperfusion of the infarct related coronary artery is achieved. Thus, we hypothesize that myocardium at risk of necrosis in the infarct area may be preserved by GIK infusion and subsequent reperfusion therapy. Therefore, the aim of our study is to demonstrate that GIK infusion prior to a primary PTCA in the acute phase of infarction results in infarct size reduction which can be clinically observed as an improvement of left ventricular function. For this purpose 100 patients undergoing primary PTCA will be randomized to GIK infusion or to saline infusion. It is expected that the endsystolic volume (as a measure of global left ventricular function) after three months is significantly lower in the GIK treated PTCA group than in the saline treated PTCA group. The rationale for the choice of this patient group is that reperfusion can clearly be defined and is optimal compared to thrombolytic therapy. Using thrombolytic therapy reperfusion can be obtained but the moment of reperfusion may not be accurately assessed and often a severe residual stenosis is present. However, if the results of this study clearly demonstrate a benefit of GIK treatment, in later studies the use of GIK in patients undergoing thrombolytic therapy can be studied. The secondary endpoint will be other measures of infarct size based on a) the ventriculogram during catheterization, b) echocardiography and c) infarct enzymes. The tertiary endpoint in this study is the flow of the infarct related coronary artery and myocardial perfusion in the infarct territory. It has been observed that coronary flow immediately after opening of the vessel may not be normal (no reflow or slow reflow). This can be explained by microvascular injury due to infarction, thrombo-embolic plugging of the distal infarct-related coronary artery and release of vasoconstricting agents by the thrombotic material resident at the ruptured plaque. As we expect a reduction of infarct size by GIK, coronary flow and coronary flow reserve of the infarct-related artery may be higher directly after PTCA and after 3 months. More important than coronary flow is myocardial perfusion. Although we cannot measure myocardial perfusion, there are surrogates available, derived from coronary angiography: the so-called TIMI flow, the TIMI frame count and extent of myocardial blush. These parameters can routinely be obtained from the angiogram directly after PTCA. Another indirect measure of the success of reperfusion is the disappearance of the ST-segment elevation and depression on the ECG after PTCA: these parameters will also be compared between the GIK and saline treated group. It is expected that coronary flow reserve, myocardial perfusion and ST-segment resolution is higher in the GIK treated group than in the saline treated group. Finally, the activation of immunological processes after infarction will be measured in the study. Recent data suggest that reperfusion of ischemic myocardium itself may induce inflammatory reactions, which, among others, involve further activation of complement, neutrophils and oxygen radicals. These inflammatory reactions may damage the cardiac tissue and limit the beneficial effects of a restored circulation (reperfusion injury). Therefore we will


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. The atherogenic effects of hyperhomocysteinemia may be preceded by endothelial dysfunction. There is no gold standard for measuring endothelial dysfunction. Measurement of vWF in plasma is an accepted method. New markers of endothelial dysfunction are the adhesion molecules (sVCAM-1, ICAM-1 and E-selectin). Significant relationships have been shown of soluble CAMs with atherosclerosis and cardiovascular events, and increasing evidence supports the role of soluble CAMs as molecular markers of atherosclerosis. Microalbuminuria is a strong predictor of cardiovascular morbidity and mortality. The pathophysiological basis of the association of microalbuminuria and cardiovascular disease is unclear, but endothelial dysfunction may be the missing link. Microalbuminuria and hyperhomocysteinemia are both associated with an increase of the vWF concentration, and sVCAM-1 levels are associated with the development of microalbuminuria. Studies addressing the association of hyperhomocysteinemia and microalbuminuria are not entirely consistent, but suggest that increased homocysteine levels are associated with an increased prevalence of microalbuminuria, as recently confirmed by Jager et al. in a prospective study. If hyperhomocysteinemia causes endothelial dysfunction, it may be that reduction of hyperhomocysteinemia by folic acid improves endothelial dysfunction. This could be reflected in reduction of microalbuminuria and of plasma levels of vWF and sCAMS. In this study we examine the effect of intervention with folic acid on microalbuminuria, vWF and sCAMs in patients with diabetes mellitus type 2 and mild hyperhomocysteinemia. These patients are divided into 2 groups, matched for sex and age, stratified for previous cardiovascular events and lipid status, and randomised for treatment with folic acid once a day 5 mg or placebo. After 0, 3, and 6 months the difference will be determined between the folic acid group and the placebo group with regard to fasting homocysteine, vWF antigen concentration, sCAMs, interleukin-6, TNF-alpha, and urinary microalbumin/creatinine ratio. 53 patients have participated, of whom 9 patients were excluded due to change of medication or loss in follow-up. Blood biochemical analyses are performed at this time.


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Various theories have been proposed to explain the hyperglycemia-induced pathogenesis of vascular complications of diabetes. These include the activation of the polyol pathway, redox potential alterations, a de novo synthesis of diacylglycerol and activation of PKC and the nonenzymatic glycation. Furthermore, hyperglycemia increased the production of reactive oxygen species (ROS) inside the cells. Michael Brownlee and coworkers demonstrated recently that normalizing the glucose-induced increased levels of mitochondrial ROS prevented the activation of PKC, formation of AGEs, sorbitol accumulation and NFkB activation. Therefore, ROS produced by the mitochondrial electron transport chain seems to be a causal link between elevated levels of glucose and the pathways responsible for hyperglycemia-induced vascular damage. However, it is not clear how superoxide anion radicals are produced. The working hypothesis of this study is that increased concentrations of the glycolytic intermediate methylglyoxal (MGO) explain the hyperglycemia-induced alterations in endothelial cells by increasing ROS release followed by a ROS-dependent formation of AGEs, PKC activation and NFkB activation. Methylglyoxal is increased in diabetes mellitus and has been identified as an important intermediate in the non-enzymatic glycation. We have shown in vitro that MGO-modified proteins induced ROS. MGO primarily reacts with arginine residues. A possible second mechanism of MGO-induced oxidative stress is via an inhibition of the adenine nucleotide translocator (ANT) in mitochondria. The ANT is involved in the uptake of ADP and export of ATP. Inhibition of ANT will lead to low ADP and high ATP levels inside the mitochondria and high ADP and low ATP in the cytosol and may stimulate ROS production. Because of the arginine residues involved in the active site of ANT, MGO may modify the ANT and as such may stimulate mitochondrial ROS production. The objectives are: - To determine the accumulation of methylglyoxal and methylglyoxal adducts in different tissues in STZ rats; - To determine in isolated rat liver mitochondria the effect of methylglyoxal on ADT and ATP concentrations and production of ROS; - To study in in vitro experiments whether methylglyoxal and methylglyoxal adduct are increased in glucose-incubated endothelial cells and may lead to an increase in ROS production. With these biochemical studies more insight will be gained into the significance of MGO in the initiation of hyperglycemia-induced endothelial dysfunction. In addition to the present proposal, studies are going on with the aim to test to what extent MGO-adducts in type 1 diabetic patients, as measured with specific monoclonal antibodies in plasma samples, are related to vascular complications.


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Pulmonary hypertension is a rare, progressive and often fatal disease, for which the therapeutic options are limited. The study of pulmonary hypertension and the evaluation of new therapeutics have been hindered until now by a lack of a quantitative description of the cardiac and pulmonary circulation. The purpose of our study will be to identify the quantitative effects of the principal cardiac and pulmonary vascular variables involved in the development of pulmonary hypertension making it possible to direct new therapeutical strategies by means of a rational approach. Therefore, we use a mathematical model based on flow and pressure wave analysis. Flow waves in the pulmonary artery are measured by means of MRI whereas pressure waves are measured by means of right heart catherisation. After assessing the validity of the model, the clinical value of this model-based approach will be studied with special focus on the differential diagnosis of pulmonary hypertension and in the study the effects of new therapeutics.


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Renal ischemia/reperfusion (I/R) and endotoxemia are the major sequential or concurrent clinical insults resulting in acute renal failure (ARF). Although both conditions may involve necrosis or apoptotis induction by oxygen free radical formation and neutrophil sequestration/activation, cause-effect relations are not clear, and - in fact - might differ substantially among the conditions. In addition, the final downstream signaling events leading to, potentially preventable or reversible, apoptosis in these conditions have not yet been resolved. The main research objectives of this proposal, therefore, are i) to establish the susceptibility for I/R damage (apoptosis vs. necrosis) of the different morphological and functional units (i.e. vessels, glomeruli and tubuli) in the kidney; ii) to investigate the effects of inflammation, i.e. endotoxin exposure; iii) to determine the contribution and relative importance of the signal transduction routes involved in apoptosis induction in the conditions; and iv) to investigate the effects on of specific caspase inhibitors on apoptosis induction pathways. To reach these goals we will use - among other things - the newly implemented 3D live-cell digital imaging microscope (3D-DIM) facility. It concerns in vitro studies of signaling molecules in isolated vessels as well as in cultures of glomerular mesangial and tubular cells. This may be the first step in enhancing our understanding of the intracellular mechanisms provoking ARF.


Grant
Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

Epidemiological studies have consistently shown an inverse association between weight at birth and systolic blood pressure in later life. This association has been attributed to intrauterine malnutrition that impairs intrauterine growth and causes raised blood pressure in later life. The alternative view is that genetic factors influencing both birth weight and systolic blood pressure could explain the relationship between these two factors. Twin studies offer a unique opportunity to distinguish between intrauterine and genetic influences. Several recent twin studies suggested that genetic factors play an important role in the association between birth weight and blood pressure. The (patho)physiological basis for the apparent elevation in blood pressure associated with low birth weight is unknown. Intra-uterine malnutrition and/or a genetic predisposition may lead to abnormal development of the microcirculation. Recent studies indeed demonstrated that microvascular function is impaired in subjects with a low birth weight, but it is unknown whether the association between birth weight and microvascular function is due to intrauterine or genetic factors. To examine the possible role for microvascular function in the birth weight-blood pressure relation and the possible influence of genetic factors, we will investigate microvascular function and blood pressure in 10 monozygotic and 10 dizygotic twin pairs with a large intrapair difference in birth weight.

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Loading Institute For Cardiovascular Research Vu Icar Vu collaborators