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

Huan Tao, Jiansheng Huang, Patricia G. Yancey, Valery Yermalitsky, John L. Blakemore, Youmin Zhang, Lei Ding, Irene Zagol-Ikapitte, Fei Ye, Venkataraman Amarnath, Olivier Boutaud, John A. Oates, L. Jackson Roberts, Sean S. Davies and MacRae F. Linton ()
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Huan Tao: Vanderbilt University School of Medicine
Jiansheng Huang: Vanderbilt University School of Medicine
Patricia G. Yancey: Vanderbilt University School of Medicine
Valery Yermalitsky: Vanderbilt University School of Medicine
John L. Blakemore: Vanderbilt University School of Medicine
Youmin Zhang: Vanderbilt University School of Medicine
Lei Ding: Vanderbilt University School of Medicine
Irene Zagol-Ikapitte: Vanderbilt University School of Medicine
Fei Ye: Vanderbilt University School of Medicine
Venkataraman Amarnath: Vanderbilt University School of Medicine
Olivier Boutaud: Vanderbilt University School of Medicine
John A. Oates: Vanderbilt University School of Medicine
L. Jackson Roberts: Vanderbilt University School of Medicine
Sean S. Davies: Vanderbilt University School of Medicine
MacRae F. Linton: Vanderbilt University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17915-w

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