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A novel mechanism for ART-associated dyslipidemia and atherosclerosis

ART 相关血脂异常和动脉粥样硬化的新机制

基本信息

批准号：
9273599
负责人：
Changcheng Zhou
金额：
$ 37.35万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9273599
关键词：
Adverse effects Agonist Amprenavir Animal Model Anti-Retroviral Agents Apolipoprotein E Arterial Fatty Streak Atherosclerosis Awareness CD36 gene Cardiovascular Diseases Cells Chemicals Cholesterol Chronic Clinical Comorbidity Development Diet Disease Dose Drug Regulations Dyslipidemias Foam Cells Follow-Up Studies Gene Expression Generations Goals HIV HIV Infections HIV Protease Inhibitors HIV therapy Health Heart Homeostasis Hyperlipidemia In Vitro Individual Infection Inflammation Intestines Knockout Mice Laboratories Lipids Liver Long-Term Survivors Longevity Lopinavir Mediating Modeling Molecular Morbidity - disease rate Mus Nuclear Receptors Pathway interactions Patients Pharmaceutical Preparations Pilot Projects Protease Inhibitor Receptor Activation Regulation Risk Ritonavir Role SXR receptor Signal Pathway Testing Therapeutic Uses Wild Type Mouse Xenobiotic Metabolism Xenobiotics absorption antiretroviral therapy atherogenesis base cardiovascular disorder risk cholesterol transporters defined contribution disorder risk drug metabolism efavirenz experimental study in vivo insight macrophage mortality mouse model non-nucleoside reverse transcriptase inhibitors novel pregnane X receptor public health relevance receptor function scavenger receptor sensor survivorship uptake

项目摘要

DESCRIPTION (provided by applicant): The rise in long-term HIV survivorship as a result of the introduction of effective antiretroviral therapy (ART) over the past decades has generated new awareness of the sequelae of both HIV infection and of the therapeutics used to treat HIV patients. Accumulating evidence of comorbidities associated with HIV infection and treatment with antiretroviral (ARV) drugs includes significant dyslipidemia and elevated risk of developing atherosclerotic cardiovascular disease (CVD). The goal of this project is to investigate a novel mechanism of ART-associated dyslipidemia and cardiovascular disease (CVD). Several ARV drugs have been identified as potent agonists for the pregnane X receptor (PXR), a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. PXR functions as a xenobiotic sensor that induces expression of genes required for xenobiotic metabolism in the liver and intestine. In the past decade, the function of PXR in the regulation of drug and xenobiotic metabolism has been extensively studied by many laboratories and the role of PXR as a xenobiotic sensor has been well established. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice. Preliminary studies demonstrated that HIV protease inhibitor amprenavir activates PXR and induces hyperlipidemia in wild- type mice but not in PXR-deficient mice; furthermore, follow-up study of currently used first-line ARV drugs subsequently found that these drugs activated PXR and induced PXR-mediated gene expression. The goal of this project is to generate novel mechanistic insights into ART-associated dyslipidemia and risk of CVD. Our central hypothesis is that long-term treatment with ARV drugs that activate PXR will lead to aberrant lipid homeostasis and accelerated atherosclerosis. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on lipid homeostasis; 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induce hyperlipidemia; and 3) Determine the impact of ARV drug-mediated PXR activation on macrophage functions and atherosclerosis development. These studies will provide critical mechanistic insights and new understandings of ART-associated dyslipidemia and CVD risk and will have direct clinical consequences for patients undergoing long-term treatment with PXR agonistic drugs.