Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr\u2212/\u2212 mice

Huan Tao,Venkataraman Amarnath,John L Blakemore,Lei Ding,L Jackson Roberts,Olivier Boutaud,Jiansheng Huang,Patricia G Yancey,Irene Zagol-Ikapitte,Sean S Davies,Youmin Zhang,Valery Yermalitsky,Macrae F Linton,Fei Ye,John A Oates

doi:10.1038/s41467-020-17915-w

Huan Tao, Venkataraman Amarnath + Show 13 more

Open Access

https://doi.org/10.1038/s41467-020-17915-w

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Journal: Nature Communications	Publication Date: Aug 14, 2020
Citations: 44	License type: open-access

Affiliation: Vanderbilt University

Abstract

Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. Humans with familial hypercholesterolemia (FH) have increased lipoprotein dicarbonyl adducts and dysfunctional HDL. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in Ldlr−/− mice, a model of FH. Compared to hypercholesterolemic Ldlr−/− mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in en face aortas, without changing plasma cholesterol. Ldlr−/− mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. Importantly, 2-HOBA reduces the MDA- and IsoLG-lysyl content in atherosclerotic aortas versus 4-HOBA. Furthermore, 2-HOBA reduces inflammation and plaque apoptotic cells and promotes efferocytosis and features of stable plaques. Dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects in a murine FH model, supporting its potential as a therapeutic approach for atherosclerotic cardiovascular disease.

Highlights

Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins
We found that HDL from humans with severe familial hypercholesterolemia (FH) contained increased MDA adducts vs control subjects, and that FHHDL were extremely impaired in reducing macrophage cholesterol stores
Oxidative stress-induced lipid peroxidation has been implicated in the development of atherosclerosis

Summary

Introduction

Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in Ldlr−/− mice, a model of FH. Compared to hypercholesterolemic Ldlr−/− mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in en face aortas, without changing plasma cholesterol. Ldlr−/− mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. One-way ANOVA with Bonferroni’s post hoc test, p values of 2-HOBA vs 4-HOBA and 2-HOBA vs vehicle are >0.9999 for both cholesterol and triglyceride levels. HDL protects against atherosclerosis via multiple roles including promoting cholesterol efflux, preventing LDL oxidation, maintaining endothelial barrier function, and by minimizing cellular oxidative stress and inflammation[1,4,6]. Evidence has mounted that oxidative modification of HDL compromises its functions, and studies suggest that oxidized HDL is proatherogenic[1,6,9]

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