Lectin-like oxidized low-density lipoprotein receptor-1 promotes endothelial dysfunction in LDL receptor knockout background

Atheroscler Suppl. 2017 Nov:30:294-302. doi: 10.1016/j.atherosclerosissup.2017.05.020.

Abstract

Objective: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date.

Methods: Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr-/-) mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph.

Results: WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P < 0.0001) in bLOX-1tg and WT mice without HDL-elevation in bLOX-1tg mice. Gonadal fat pad weight was 1.7 and 1.2-fold increased on CD and WD in bLOX-1tg mice compared to WT. LOX-1 overexpression impaired endothelial function by 15-16% (P < 0.05) on CD and WD. Crossing bLOX-1tg mice into Ldlr-/- background strongly elevated total (∼6-fold) and LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr-/- mice (Effmax: 56.7 ± 23.0%) compared to WT (Effmax: 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Effmax: 76.7 ± 12.9%, P < 0.05) and Ldlr-/- mice (Effmax: 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr-/- mice were detectable when comparing all genotypes.

Conclusion: Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis.

Keywords: Dyslipidemia; Endothelial dysfunction; LOX-1; Reactive oxygen species.

MeSH terms

  • Animals
  • Aorta, Thoracic / metabolism*
  • Aorta, Thoracic / physiopathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism*
  • Aortic Diseases / pathology
  • Aortic Diseases / physiopathology
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Blood Glucose / metabolism
  • Cattle
  • Diet, Western
  • Disease Models, Animal
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Genetic Predisposition to Disease
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / metabolism
  • Hypertriglyceridemia / genetics
  • Hypertriglyceridemia / metabolism
  • Lipids / blood
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type I / genetics
  • Nitric Oxide Synthase Type I / metabolism
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Phenotype
  • Plaque, Atherosclerotic
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Scavenger Receptors, Class E / genetics
  • Scavenger Receptors, Class E / metabolism*
  • Vasodilation*

Substances

  • Blood Glucose
  • Lipids
  • Receptors, LDL
  • Scavenger Receptors, Class E
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type III
  • Nos1 protein, mouse
  • Nos3 protein, mouse