Markers And Mechanisms Of Vascular Disease In Diabetes

Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425

Grant 5P01HL055782-10 from National Heart, Lung, And Blood Institute, IRG: HLBP

Abstract: Vascular Disease is the leading cause of complications and death in patients with diabetes. Risk markers and underlying mechanisms have not been fully elucidated, and may differ from those in non-diabetic individuals. The unifying theme for the Program Project is that hyperglycemia and insulin resistance alter a number of biological processes which interact in vicious cycles to accelerate atherogenesis and are consequently major underlying risk factors for vascular disease. The overall objectives are to define these unique processes and to elucidate underlying biochemical, metabolic, and genetic determinants of vascular disease complications in diabetes. Over the past 4 years, we have collaborated with the DCCT/EDIC Study Group, and have made novel observations regarding vascular disease pathogenesis in Type I Diabetes. This work has focused our studies on specific pathogenic processes. We will also incorporate a Type 2 Diabetes cohort from the VA Cooperative Study, "Glycemic Control and the Complications of Diabetes, Type 2", with high vascular disease event rates. These collaborations provide a unique opportunity to address the pathogenesis of accelerated atherogenesis in the two main types of diabetes, and will greatly augment the scientific knowledge that will be gained in the conduct of these world-class prospective trials. The Program Project has 4 projects and 3 cores. Project 1 will assess lipoproteins, glycoxidative stress, and inflammation as risk factors in studies involving Type 1 and 2 Diabetes patients and cultured cell systems. Based on preliminary data, changes in the NMR lipoprotein subclass profile will be emphasized. Project 2 will elucidate interactions between inflammation, modifications of lipoproteins, and autoimmunity in vascular disease risk. These novel concepts are also based upon exciting preliminary data pertaining to LDL-antibody complexes. Project 3 will pursue interesting preliminary data and define the role of the kallikrein-kinin system in vascular disease complications, with effects on mitogenesis and matrix production. Project 5 will assess the role of the Insulin Resistance Syndrome and novel factors secreted from adipocytes in the pathophysiology of biochemical risk factors and cardiovascular complications. Cores include an Biostatistics and Epidemiology which will link with the trials data coordinating centers, and Molecular and Statistical Genetics Core. There is true synergism among the projects at both scientific and logistical levels. The Program Project design allows for interactions among multi-disciplinary investigators studying the same cohorts, which will define how multiple pathological processes interact at the level of the arterial wall to promote atherosclerosis.

Keywords: cardiovascular disorder epidemiology, diabetes mellitus, diabetes risk, diabetic angiopathy, clinical research

Project start date: 1996-09-30

Project end date: 2008-08-31

5P01HL055782-10 (2005): $1894024

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Markers And Mechanisms Of Vascular Disease In Diabetes

Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425

Grant 5P01HL055782-09 from National Heart, Lung, And Blood Institute, IRG: HLBP

Abstract: Vascular Disease is the leading cause of complications and death in patients with diabetes. Risk markers and underlying mechanisms have not been fully elucidated, and may differ from those in non-diabetic individuals. The unifying theme for the Program Project is that hyperglycemia and insulin resistance alter a number of biological processes which interact in vicious cycles to accelerate atherogenesis and are consequently major underlying risk factors for vascular disease. The overall objectives are to define these unique processes and to elucidate underlying biochemical, metabolic, and genetic determinants of vascular disease complications in diabetes. Over the past 4 years, we have collaborated with the DCCT/EDIC Study Group, and have made novel observations regarding vascular disease pathogenesis in Type I Diabetes. This work has focused our studies on specific pathogenic processes. We will also incorporate a Type 2 Diabetes cohort from the VA Cooperative Study, "Glycemic Control and the Complications of Diabetes, Type 2", with high vascular disease event rates. These collaborations provide a unique opportunity to address the pathogenesis of accelerated atherogenesis in the two main types of diabetes, and will greatly augment the scientific knowledge that will be gained in the conduct of these world-class prospective trials. The Program Project has 4 projects and 3 cores. Project 1 will assess lipoproteins, glycoxidative stress, and inflammation as risk factors in studies involving Type 1 and 2 Diabetes patients and cultured cell systems. Based on preliminary data, changes in the NMR lipoprotein subclass profile will be emphasized. Project 2 will elucidate interactions between inflammation, modifications of lipoproteins, and autoimmunity in vascular disease risk. These novel concepts are also based upon exciting preliminary data pertaining to LDL-antibody complexes. Project 3 will pursue interesting preliminary data and define the role of the kallikrein-kinin system in vascular disease complications, with effects on mitogenesis and matrix production. Project 5 will assess the role of the Insulin Resistance Syndrome and novel factors secreted from adipocytes in the pathophysiology of biochemical risk factors and cardiovascular complications. Cores include an Biostatistics and Epidemiology which will link with the trials data coordinating centers, and Molecular and Statistical Genetics Core. There is true synergism among the projects at both scientific and logistical levels. The Program Project design allows for interactions among multi-disciplinary investigators studying the same cohorts, which will define how multiple pathological processes interact at the level of the arterial wall to promote atherosclerosis.

Keywords: cardiovascular disorder epidemiology, diabetes mellitus, diabetes risk, diabetic angiopathy, clinical research

Project start date: 1996-09-30

Project end date: 2006-08-31

5P01HL055782-09 (2004): $1849846

5P01HL055782-08 (2003): $1807267

5P01HL055782-07 (2002): $1385266

MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN DIABETES

Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425

Grant 5P01HL055782-100002 from National Heart, Lung, And Blood Institute, IRG:

Abstract: High levels of immune complexes (IC) containing oxLDL predict the development of macrovascular complications in type 1 diabetes (DM) and are associated with coronary artery disease (CAD) in type 2 DM. Data obtained during the on-going funding period shows that the levels of oxLDL-IC are significantly associated with internal carotid intima-medial thickness (p<0.001, n=853) and are significantly increased in type 1 DM with micro/macroalbuminuria and moderate/severe retinopathy, compared with levels of LDL-IC in patients with normalalbuminuria or mild retinopathy (p<0.013 and 0.0006, respectively). The levels of LDL-IC are strongly correlated with serum Apo B levels, serum Lp(a) levels and serum triglycerides (p<0.0001, n=853) and have also a significant direct correlation (p<0.0001, n=854) with C-reactive protein and with soluble ICAM-1 (p<0.02, n=455). LDL-IC correlate as well with Hb A1c (p<0.005, n=888), suggesting that glycemic control will impact the formation of LDL-IC. We have also demonstrated in patients with micro or macroalbuminuria that antibodies (Ab) against ox-LDL isolated from oxLDL-IC have a higher affinity than the free Ab present in sera of the same patients. This suggests that one critical factor determining the pathogenicity of oxLDL-IC is the synthesis of oxLDL Ab of moderate affinity, able to form stable IC with pro-inflammatory potential. Because Chlamydia pneumonia has been shown to have a strong epidemiological correlation with CAD and one of its major antigens is a cell wall lipopolysaccharide (LPS), that when released into circulation is transported by lipoproteins, we plan to investigate whether chlamydia LPS is present in IC purified from sera of diabetic patients. The main goal of this proposal is to compare the levels of soluble adhesion molecules (sCAM) and the levels and characteristics of LDL-IC isolated from the sera of a type 2 DM cohort (Prospective VA Cooperative Trial) under intensive or standard glycemic control. We hypothesize that, similarly to type 1 DM, LDL-IC in type 2 DM have pro-inflammatory characteristics and are associated with micro and macrovascular complications. We further hypothesize that intensive glycemic control will impact the formation of IC and the release of CAMs into the circulation. We also propose to determine whether or not patients from the DCCT/EDIC cohort (type 1 DM) and VA cohort 2 (type 2 DM) that develop macrovascular disease, retinopathy and micro/macro-albuminuria have a higher incidence of chronic C. pneumoniae infection and to characterize the IC present in the serum of patients from both cohort 1 and 2 that develop macrovascular disease/nephropathy/retinopathy for oxLDL, oxLDL-Lp(a), AGE-LDL, Chlamdial-LPS or DNA, as well as Ab against these antigens. We will also determine the affinity and isotype distribution of Ab isolated from IC, to evaluate their pro-inflammatory potential. Finally, we will assess possible pathogenic mechanisms triggered by these IC by investigating their ability to induce accumulation of cholesterol in macrophages, kidney mesangial cells and retinal pericytes and to activate these cells leading to the expression of cytokines, sCAM and metalloproteinases. Incorporation of our study into the Program allows us to compare LDL-IC levels with the inflammatory markers and endothelial cell dysfunction markers measured in other projects and that will result in a better understanding of the significance of auto-immune responses to modified forms of LDL to the pathogenesis of atherosclerosis in diabetes.

Keywords: autoimmune disorder, blood lipoprotein metabolism, immune complex, low density lipoprotein, noninsulin dependent diabetes mellitus, bacterial antigen, blood glucose, cardiovascular disorder epidemiology, cell adhesion molecule, chlamydial disease, cholesterol, diabetic angiopathy, inflammation, lipopolysaccharide, macrophage, oxidized lipid, vascular endothelium, clinical research, human subject

MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN IDDM

Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425

Grant 5P01HL055782-050002 from National Heart, Lung, And Blood Institute, IRG:

Keywords: atherosclerosis, autoimmune disorder, blood lipoprotein metabolism, insulin dependent diabetes mellitus, low density lipoprotein, autoantibody, cardiovascular disorder epidemiology, cell adhesion molecule, diabetic angiopathy, immune complex, macrophage, clinical research, human subject

Project start date: 2000-09-01

Project end date: 2001-08-31

MACROPHAGE ACTIVATION AND LIPOPROTEIN METABOLISM

Maria F Lopes-virella, Professor
Medicinemedical University Of South Carolina
office Of Research And Sponsored Programs
charleston, Sc 29425

Grant 5R01HL046815-06 from National Heart, Lung, And Blood Institute, IRG: MET

Abstract: We have demonstrated that the uptake of LDL-containing immune complexes (LDL-IC) by human monocyte-derived macrophages induces the transformation of these cells into foam cells and promotes their activation leading to a paradoxical increase in LDL receptor cell surface expression and to the release of cytokines. In this proposal we plan to analyze the molecular mechanisms responsible for the increase in LDL receptor cell surface expression. We will determine whether the increase in LDL receptor expression, observed in human macrophages stimulated by LDL-containing immune complexes (LDL-IC), is due to increased transcription of the LDL receptor gene, increased mRNA stability, increased mRNA translation, decreased LDL receptor protein degradation or increased translocation of the LDL receptor protein to the cell membrane. We will also investigate whether this increase in LDL receptor expression is secondary to a decrease in the intracellular cholesterol regulatory pool and if so, whether the depletion in this regulatory pool is secondary to enhanced sterol mobilization to the ACAT substrate pool. Furthermore, we will determine whether factors released during macrophage activation mediate or facilitate the increase in LDL receptor cell surface expression. We will also investigate whether the stimulation of LDL receptor cell surface expression is a consequence of the uptake of the LDL-containing immune complexes by a specific Fc receptor subtype (Fc-gamma-RI, Fc-gamma-RII or Fc-gamma-RIII). Since HMGCoA reductase activity and LDL receptor activity usually have a coordinate regulation, we will determine whether HMGCoA reductase activity is also increased in LDL-IC-stimulated macrophages. This project will involve cell culture, cell isolation and cell fractionation procedures, studies of intracellular lipid metabolism, receptor binding studies, immunoblotting and molecular biology techniques. Our overall objective is to provide insight into the mechanisms by which anti-LDL antibodies and macrophage activation may contribute to the development(acceleration of the arteriosclerotic process

Keywords: biological signal transduction, blood lipoprotein metabolism, leukocyte activation /transformation, low density lipoprotein receptor, macrophage, receptor expression cholesterol, enzyme activity, enzyme inhibitor, genetic regulation, genetic regulatory element, genetic transcription, immune complex, mitogen activated protein kinase, reporter gene, second messenger, transcription factor DNA footprinting, antisense nucleic acid, gel mobility shift assay, human tissue, northern blotting, polymerase chain reaction, tissue /cell culture, western blotting

Project start date: 1994-08-01

Project end date: 2001-11-30

5R01HL046815-06 (2001): $235954

5R01HL046815-05 (2000): $229081

2R01HL046815-04A2 (1999): $225409

MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN IDDM

Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425

Grant 1P01HL055782-020002 from National Heart, Lung, And Blood Institute, IRG:

Keywords: atherosclerosis, autoimmune disorder, blood lipoprotein metabolism, insulin dependent diabetes mellitus, low density lipoprotein, autoantibody, cardiovascular disorder epidemiology, cell adhesion molecule, diabetic angiopathy, immune complex, macrophage, clinical research, human subject

Project start date: 1997-09-15

Project end date: 1998-08-31

MACROPHAGE ACTIVATION AND LIPOPROTEIN METABOLISM

Maria F Lopes-virella, Professor
Medicinemedical University Of South Carolina
office Of Research And Sponsored Programs
charleston, Sc 29425

Grant 5R01HL046815-03 from National Heart, Lung, And Blood Institute, IRG: MET

Project start date: 1994-08-01

Project end date: 1998-07-31

5R01HL046815-03 (1996): $217577

MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN IDDM

Maria F Lopes-virella, Professor
Institution:

Grant 1P01HL055782-01A10002 from National Heart, Lung, And Blood Institute, IRG:

Keywords: atherosclerosis, autoimmune disorder, blood lipoprotein metabolism, insulin dependent diabetes mellitus, low density lipoprotein, autoantibody, cardiovascular disorder epidemiology, cell adhesion molecule, diabetic angiopathy, immune complex, macrophage, clinical research, human subject