2. Academic Validation
  3. Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr-/- mice

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

  • Nat Commun. 2020 Aug 14;11(1):4084. doi: 10.1038/s41467-020-17915-w.
Huan Tao  # 1,  Jiansheng Huang  # 1,  Patricia G Yancey 1,  Valery Yermalitsky 2,  John L Blakemore 1,  Youmin Zhang 1,  Lei Ding 1,  Irene Zagol-Ikapitte 3,  Fei Ye 4,  Venkataraman Amarnath 2,  Olivier Boutaud 2,  John A Oates 2 3,  L Jackson Roberts 2nd 2,  Sean S Davies 2,  MacRae F Linton 5 6
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
  • 2 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
  • 3 Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
  • 4 Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
  • 5 Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. macrae.linton@vanderbilt.edu.
  • 6 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. macrae.linton@vanderbilt.edu.
  • # Contributed equally.
PMID: 32796843 DOI: 10.1038/s41467-020-17915-w
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.

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