Mechanisms for Dysfunctional HDL Formation in Familial Hypercholesterolemia

Summary

Principal Investigator: Macrae F Linton
Abstract: DESCRIPTION (provided by applicant): Anti-atherogenic functions of HDL include mediation of reverse cholesterol transport, and anti-oxidative and anti- inflammatory effects. Mounting evidence supports the concept that HDL function can be impaired or lost, and that dysfunctional HDL contributes to the development of atherosclerosis. Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with severely elevated LDL levels and increased risk of premature coronary artery disease (CAD). Both heterozygous and homozygous FH have low HDL, but this finding has not received much attention, and the increased CAD risk is attributed to the elevated LDL levels. We have recently discovered that the HDL from patients with FH is dramatically pro-inflammatory. A goal of this proposal (Specific Aim 1) is to examine the hypothesis that HDL of FH patients is dysfunctional (pro-inflammatory, pro- oxidant, and/or associated with reduced efflux capacity). Isoprostanes are formed from the non-enzymatic oxidation of arachidonic acid in phospholipids of lipoproteins and cell membranes. Plasma levels of F2- isoprostanes are established in vivo markers of lipid peroxidation and oxidant stress. Interestingly, the esterified isosprostanes, (EIs) in human plasma are mainly localized to HDL, with lesser amounts associated with LDL and VLDL. Several lines of evidence support a direct role for lipid peroxidation and/or F2-isoprostanes in atherosclerotic lesion development. At present it is unknown whether the accumulation of EIs in HDL affects its atheroprotective functions. Interestingly, we have found that plasma from subjects with FH undergoing LDL apheresis has twice the amount of EIs compared to normal plasma, and that after LDL apheresis EI levels decrease by 45%. Isolevuglandins (isoLGs) are a group of g-ketoaldehydes (isoketals) that are highly reactive mediators of oxidative damage formed in parallel with isoprostanes. We will investigate whether these bioactive lipids play direct mechanistic roles in the pro-inflammatory properties of HDL in FH patients. In Specific Aim 2, we will examine the hypothesis that accumulation of bioactive lipids (F2-isoprostanes and Isolevuglandins) in HDL results in loss of anti-inflammatory function. Isoprostanes have been shown to bind to eicosanoid receptors implicated in atherogenesis, including receptors for thromboxane (TP) and prostaglandin (PG)E2 (EP2). Therefore, we will examine the hypothesis that the TP and EP2 receptors contribute to the inflammatory effects of F2-isoprostane enriched HDL. Isoketals rapidly adduct to the e-amino groups of lysines on proteins, promoting protein cross-linking and dysfunction. Therefore, we will examine the hypothesis that isolevuglandins mediate oxidative damage of HDL associated proteins resulting in impaired function of HDL cholesterol. Our results may lead to the development of new markers of HDL function, provide new pharmacologic targets for improving HDL function, and identify HDL as a target of therapy in FH patients.
Funding Period: 2012-07-23 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis
    Hagai Tavori
    From the Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Department of Medicine H T, I G, M F L, S F, and Departments of Pharmacology M F L and Pathology, Immunology and Microbiology S F, Vanderbilt University Medical Center, Nashville, TN
    Circ Res 113:1290-5. 2013

Research Grants

  1. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
  2. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
  3. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
  4. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
  5. Novel Modulators of HDL Metabolism
    Nabil A Elshourbagy; Fiscal Year: 2013
  6. Inflammation, Heart and Bone
    Grace A McComsey; Fiscal Year: 2013
  7. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
  8. Effects of particulate air pollution on HDL function and atherosclerosis
    JESUS ANTONIO ARAUJO; Fiscal Year: 2013
  9. Biophysics of HDL Dysfunction
    Mary G Sorci-Thomas; Fiscal Year: 2013
  10. HDL Function as a Biomarker for Atherosclerotic Risk in Rheumatoid Arthritis
    Christina Charles-Schoeman; Fiscal Year: 2013

Detail Information

Publications3

  1. pmc Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis
    Hagai Tavori
    From the Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Department of Medicine H T, I G, M F L, S F, and Departments of Pharmacology M F L and Pathology, Immunology and Microbiology S F, Vanderbilt University Medical Center, Nashville, TN
    Circ Res 113:1290-5. 2013
    ..We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL...

Research Grants30

  1. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
    ..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
  2. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  3. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
    ..The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of HDL. ..
  4. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  5. Novel Modulators of HDL Metabolism
    Nabil A Elshourbagy; Fiscal Year: 2013
    ..As part of this Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of selected compounds to increase the HDL-C level using in vivo animal models. ..
  6. Inflammation, Heart and Bone
    Grace A McComsey; Fiscal Year: 2013
    ..This study is novel in this population, and will have significant implications in future management of people living with HIV, specifically in better refining the indication of statin therapy in primary cardiovascular prevention. ..
  7. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  8. Effects of particulate air pollution on HDL function and atherosclerosis
    JESUS ANTONIO ARAUJO; Fiscal Year: 2013
    ....
  9. Biophysics of HDL Dysfunction
    Mary G Sorci-Thomas; Fiscal Year: 2013
    ..Development of these novel assays will make it possible, for the first time, to perform large clinical studies to fully test the idea that dysfunctional HDL is better indicator of atherosclerotic risk. ..
  10. HDL Function as a Biomarker for Atherosclerotic Risk in Rheumatoid Arthritis
    Christina Charles-Schoeman; Fiscal Year: 2013
    ..End of Abstract) ..
  11. Novel mechanisms of niacin to improve HDL function: Role of myeloperoxidase
    Moti L Kashyap; Fiscal Year: 2013
    ..3. Define cellular mechanism of action of niacin on: MPO-mediated oxidative modification of HDL- apoAI, formation of "dysfunctional HDL", and improvement in HDL's anti-atherogenic properties. ..
  12. Inflammation, Atherosclerosis and ApoA-I
    Mary G Sorci-Thomas; Fiscal Year: 2013
    ..These studies will likely provide new targets for therapeutic interventions to control the inflammatory processes that exacerbate atherosclerosis. ..
  13. The Metabolic Impact of Congenital Heterozygous ApoC-III Deficiency in Humans
    TONI ILANA POLLIN; Fiscal Year: 2013
    ..This project will look more closely at the effects of the deficiency on human metabolism to better understand the function of the apoC-III protein and its potential as a drug target. ..
  14. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  15. Lipoprotein Structure and Function by Individual Particle Electron Tomography
    Gang Ren; Fiscal Year: 2013
    ....
  16. Control of Sterol and Lipoprotein Homeostasis by miRNA
    Angel Baldán; Fiscal Year: 2013
    ..The results of these studies might lead to novel, improved ways to manage patients with hypercholesterolemia and/or patients with cholestasis. ! ..
  17. Resveratrol as an Innovative Cardiovascular Therapeutic Strategy in Lupus
    Allison B Reiss; Fiscal Year: 2013
    ..To validate our hypothesis that resveratrol impedes development of atherosclerosis via effects on cholesterol flux in the vessel wall, we will examine the vasculature in vivo in this animal model prior to consideration of human testing. ..
  18. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  19. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  20. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  21. MicroRNAs as physiological and pathological regulators of cholesterol homeostasis
    Kathryn J Moore; Fiscal Year: 2013
    ..These studies may uncover novel therapeutic strategies for the treatment of cardiovascular disease. ..
  22. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  23. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..