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Re-evaluating the role of HDL in coronary artery disease (RETRO HDL)

重新评估 HDL 在冠状动脉疾病中的作用 (RETRO HDL)

基本信息

批准号：
9121668
负责人：
Tina Costacou
金额：
$ 58.57万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9121668
关键词：
16q22 Acute Acute-Phase Proteins Alleles Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Binding Biochemical Biological Assay Blood Circulation Cardiovascular Diseases Cholesterol Collaborations Complement Complex Complications of Diabetes Mellitus Coronary Arteriosclerosis Data Development Diabetes Mellitus Epidemiology Excision Exhibits Functional disorder Future Gender General Population Genes Genetic Polymorphism Genotype Haptoglobins Heme Heme Iron Hemoglobin High Density Lipoprotein Cholesterol High Density Lipoproteins Human Incidence Individual Inflammation Insulin-Dependent Diabetes Mellitus Intervention Studies Light Lipids Measures Mediating Methods Minor Nature Oxidation-Reduction Oxidative Stress Patients Phase Physiology Plasma Proteins Play Polymers Population Property Proteins Proteomics Reporting Research Risk Risk Factors Role Sterols Testing Tissues Vitamin E Woman cardiovascular disorder risk cardiovascular risk factor cohort coronary artery calcification diabetic dimer disorder risk follow-up gender difference haptoglobin-hemoglobin complex improved interest macrophage men non-diabetic novel oxidation particle prevent public health relevance receptor reverse cholesterol transport trend uptake young adult

项目摘要

DESCRIPTION (provided by applicant): Individuals with type 1 diabetes (T1D) are at greatly increased risk of coronary artery disease (CAD) compared to the general population, despite only minor differences in traditional lipid and other cardiovascular risk factors. Although generally elevated in T1D patients, high density lipoprotein cholesterol (HDL-C) levels still inversely predict CAD risk. Surprisingly, analyses of the 18-year follow-up of our Epidemiology of Diabetes Complications (EDC) study showed an increased CAD incidence with highly elevated (>80 mg/dL) HDL-C in women, in whom no progressive protection above 50 mg/dL was noted. In men, the original strong inverse relationship held throughout the range of HDL-C levels, though only two had HDL-C above 80 mg/dL. We therefore hypothesize that these apparently contradictory findings of elevated risk in the presence of high HDL- C reflect impaired HDL functionality in T1D. Indeed, the hypothesis of dysfunctional HDL-C in terms of its most critical activity, reverse cholesterol transport, has long been proposed in T1D, although it has not been formally tested using currently available novel measures of HDL function. The recently reported association between the Haptoglobin (Hp) 2 allele and CAD incidence in diabetes is also thought, at least partially, to relate to impaired HDL function, i.e. impaired reverse cholesterol transport, in these individuals. Hp is an acute phase plasma protein whose main function is to bind free hemoglobin, thereby inhibiting heme iron release and thus reducing hemoglobin-induced oxidative tissue damage. In T1D, we showed a significantly increased CAD risk with Hp 2-2 and a linear trend toward increased risk with the number of Hp 2 alleles. Additionally, in our HapE intervention study, HDL-mediated cholesterol efflux decreased linearly with the number of Hp 2 alleles, whereas vitamin E improved efflux among Hp 2-2 carriers. Given these data, our aim, using novel sophisticated methods, is to determine: a) whether HDL function (sterol efflux) is impaired in T1D compared to non-diabetic controls (overall and by gender); b) the ability of HDL function to predict CAD in T1D by gender; and c) to what extent HDL function explains the reported Hp- CAD association in T1D. We thus propose to quantify HDL efflux capacity with macrophages using a well- validated assay, and complement these studies with state-of-the art quantification of the concentration/size of HDL particles and HDL's protein cargo (providing information on HDL's anti-inflammatory and anti-oxidative properties). The proteomic analyses, though more exploratory in nature, will provide data on HDL's anti- inflammatory/anti-oxidative properties, which would be of great interest as inflammation/oxidative stress play a role in atherosclerosis development and as Hp is an acute phase protein with anti-oxidative properties. With this research we therefore aim to further our understanding of factors that influence HDL's cardioprotective effects in patients with T1D and shed light on gender differences as well as the mechanisms underlying the increased CAD risk associated with the Hp 2 allele in this population.