Oxidant resistant apoA1 in reverse cholesterol transport, inflammation and atherosclerosis

Project: Research projectResearch Project

Description

AbstractHigh levels of high density lipoprotein-cholesterol (HDL-C) are associated with lowered risk for cardiovasculardisease (CVD) in epidemiological studies. Although several mechanisms may play a role in HDL?s protectiveeffect, HDL and its major protein constituent, apolipoprotein-AI (apoA1), are critical components of the reversecholesterol transport (RCT) pathway, in which cholesterol is removed from peripheral tissues and transferred tothe liver for excretion. In the first step of the RCT pathway, lipid-poor apoA1 acts as an acceptor for cellcholesterol and phospholipids via the cell membrane protein ABCA1, generating nascent HDL. However, notall HDL is equivalent, and several studies have reported that individuals with coronary artery disease haveHDL that is ?dysfunctional? and no longer atheroprotective. The atherosclerotic lesion is a highly oxidativeenvironment, and human lesions contain high levels of the antimicrobial enzyme myeloperoxidase (MPO),which we and others have shown can oxidize apoA1 and impair its function. We determined that the fourtryptophan residues in human apoA1 (h-apoA1) are crucial in its MPO mediated loss of cholesterol acceptorfunction. We created a novel 4WF h-apoA1 variant, in which all four tryptophan residues are replaced byphenylalanine, which is resistant to MPO-mediated loss of function. We created and characterized transgenicmice that express high levels of the 4WF h-apoA1 isoform and found that these mice were resistant toinflammation. We also created human MPO transgenic mice, which over express MPO that can be furtherinduced by zymosan treatment. Here we propose to characterize h-apoA1 modifications in mouse models andif these are modulated by inflammatory stimuli. We will also test whether the oxidant resistant 4WF apoA1isoform can better protect from inflammation and sepsis, promote reverse cholesterol transport, delayatherosclerosis progression, and promote atherosclerosis regression in mice that over express MPO, creatingan oxidative environment similar to that found in human lesions. Mechanistically, we will determine how the4WF isoform protects mice from an acute phase response, and examine if the 4WF isoform better preventsmyeloid cell proliferation and mobilization from the bone marrow leading to monocytosis and neutrophilia thatare associated with atherosclerosis progression.
StatusActive
Effective start/end date5/23/163/31/20

Funding

  • National Institutes of Health: $396,250.00

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Oxidants
Atherosclerosis
Peroxidase
Cholesterol
Inflammation
Protein Isoforms
Pre-beta High-Density Lipoprotein
Acute-Phase Reaction
Zymosan
Apolipoprotein A-I
Tryptophan
HDL Cholesterol
Transgenic Mice
Epidemiologic Studies
Coronary Artery Disease
Phospholipids
Sepsis
Membrane Proteins
Bone Marrow
Cell Proliferation