The central theme of our PPG is that HDL function is a critical determinant of atherogenesis and cardiovascular risk in chronic human disease. The goal of our research is to define the mechanisms for HDL functional loss in diseases associated with increased risk for atherosclerotic cardiovascular disease (ASCVD): Familial Hypercholesterolemia (FH), Chronic Kidney Disease (CKD) and Rheumatoid Arthritis (RA). A major hypothesis of the PPG is that dysfunctional HDL contributes to the residual inflammatory risk of cardiovascular events. Reactive dicarbonyls including MDA, IsoLG, and ONE are highly reactive species that rapidly adduct to apoAI and HDL phospholipids impairing HDL function. A major recent advance by our PPG is the discovery that two different small molecule dicarbonyl scavengers, 2-HOBA and PPM, improve HDL function, reduce LDL oxidation, and dramatically reduce atherosclerosis in Ldlr-/- deficient mice, a model of FH, in the absence of changes in plasma lipid levels. The atherosclerotic lesions showed a dramatic decrease in necrosis and inflammation and had evidence for reduced efferocytosis. Projects 1 and 4 will both explore the hypothesis that reactive carbonyl- induced HDL dysfunction will impair macrophage efferocytosis. Project 1 will test the hypothesis that dicarbonyl scavengers promote remodeling of established atherosclerosis with resolution of inflammation. These studies will set the stage for a translational proof of concept study to test the hypothesis that the dicarbonyl scavenger 2-HOBA will inhibit modification of apoAI and HDL and improve HDL functions in humans with heterozygous FH and subjects with CAD without FH. Interestingly, we have recently discovered that lipoproteins are highly- enriched with small RNAs derived from bacterial and fungal species in the microbiome and environment (msRNA). Another major theme is that msRNA carried by HDL influence HDL function and atherogenesis. Project 2 will examine the hypothesis that CKD increases mesenteric lymphatic output and apoAI harboring harmful bioactive substances (IsoLG, miRNA, msRNA) that contribute to the increased risk of ASCVD. Importantly, microbial sRNAs are present in human and mouse atherosclerotic lesions. Project 3 will examine the hypothesis that HDL removes microbial sRNAs from lesion macrophages and suppresses pro-inflammatory gene expression through retro-endocytosis and msRNA acceptance. In addition, we will target macrophage TLR7/8 activation in vivo using non-targeting locked-nucleic acids (ntLNA) to inhibit atherosclerosis progression and promote regression. Project 4 will elucidate mechanisms whereby dicarbonyl modified lipoproteins potentiate inflammation and cell death in macrophages and determine if these alterations contribute to reduced efferocytosis. Overall, the proposed studies will advance our understanding of the role of HDL function in human disease and identify new therapeutic approaches for the treatment of ASCVD. There are 4 Cores: Core A. Administrative and Biostatistics; Core B Lipoprotein and HDL Function; Core C Chemical Synthesis and Lipid Peroxidation Analytical Core; and Core D Non-Coding RNA and Bioinformatics.

Public Health Relevance

Overall Program The central theme of our PPG is that high-density lipoprotein (HDL) function is a critical determinant of atherosclerosis (plaque buildup in arteries) in chronic human diseases associated with increased risk of heart attack and stroke. Specifically, this Program will study diverse detrimental changes to HDL cargo and function, including 1) reactive dicarbonyl modifications to HDL lipids and proteins, 2) pro-inflammatory microbial small RNAs on HDL, and 3) molecular networks within a novel kidney-intestine-artery axis. In addition, we explore new therapeutic strategies to improve HDL function and reduce atherosclerosis using dicarbonyl scavengers and non-targeting locked-nucleic acids (ntLNA).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Liu, Lijuan
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Vanderbilt University Medical Center
United States
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May-Zhang, Linda S; Yermalitsky, Valery; Huang, Jiansheng et al. (2018) Modification by isolevuglandins, highly reactive ?-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function. J Biol Chem 293:9176-9187
Allen, Ryan M; Zhao, Shilin; Ramirez Solano, Marisol A et al. (2018) Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins. J Extracell Vesicles 7:1506198
Mueller, Paul A; Zhu, Lin; Tavori, Hagai et al. (2018) Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases C-C Chemokine Receptor Type 7 (CCR7) Expression in Plaque Macrophages. Circulation 138:1850-1863
Li, Kang; Rodosthenous, Rodosthenis S; Kashanchi, Fatah et al. (2018) Advances, challenges, and opportunities in extracellular RNA biology: insights from the NIH exRNA Strategic Workshop. JCI Insight 3:
Babaev, Vladimir R; Ding, Lei; Zhang, Youmin et al. (2018) Loss of 2 Akt (Protein Kinase B) Isoforms in Hematopoietic Cells Diminished Monocyte and Macrophage Survival and Reduces Atherosclerosis in Ldl Receptor-Null Mice. Arterioscler Thromb Vasc Biol :ATVBAHA118312206
Kaseda, R; Tsuchida, Y; Gamboa, J L et al. (2018) Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis. Nutr Metab Cardiovasc Dis 28:582-591
Kaseda, Ryohei; Tsuchida, Yohei; Yang, Hai-Chun et al. (2018) Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism. BMC Nephrol 19:17
Babaev, Vladimir R; Huang, Jiansheng; Ding, Lei et al. (2018) Loss of Rictor in Monocyte/Macrophages Suppresses Their Proliferation and Viability Reducing Atherosclerosis in LDLR Null Mice. Front Immunol 9:215
Byram, Kevin W; Oeser, Annette M; Linton, MacRae F et al. (2018) Exercise is Associated With Increased Small HDL Particle Concentration and Decreased Vascular Stiffness in Rheumatoid Arthritis. J Clin Rheumatol 24:417-421
Sedgeman, Leslie R; Beysen, Carine; Allen, Ryan M et al. (2018) Intestinal bile acid sequestration improves glucose control by stimulating hepatic miR-182-5p in type 2 diabetes. Am J Physiol Gastrointest Liver Physiol :

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