Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease-accelerated atherosclerosis

J Biol Chem. 2018 May 11;293(19):7238-7249. doi: 10.1074/jbc.RA117.000559. Epub 2018 Mar 26.

Abstract

Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptor-deficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products-protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and o,o'-dityrosine-were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity (i.e. increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which co-localize with lesional macrophages. These results implicate macrophage-derived MPO in CKD-accelerated atherosclerosis.

Keywords: 3-chlorotyrosine; 3-nitrotyrosine; Chronic Kidney Disease; atherosclerosis; macrophage; mass spectrometry (MS); myeloperoxidase; oxidative stress; oxidized amino acids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Atherosclerosis / blood
  • Atherosclerosis / etiology
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Blood Urea Nitrogen
  • Creatinine / blood
  • Diet, Fat-Restricted
  • Diet, High-Fat
  • Dietary Fats / administration & dosage
  • Disease Models, Animal
  • Disease Progression
  • Kidney Failure, Chronic / blood
  • Kidney Failure, Chronic / complications*
  • Kidney Failure, Chronic / physiopathology
  • Kidney Function Tests
  • Lipids / blood
  • Lipoproteins / blood
  • Macrophages / enzymology
  • Male
  • Mice
  • Mice, Knockout
  • Muscle Proteins / metabolism*
  • Nephrectomy
  • Oxidants / metabolism*
  • Oxidative Stress
  • Parathyroid Hormone / blood
  • Peroxidase / metabolism*
  • Receptors, LDL / genetics
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Vasodilation

Substances

  • Dietary Fats
  • Lipids
  • Lipoproteins
  • Muscle Proteins
  • Oxidants
  • Parathyroid Hormone
  • Receptors, LDL
  • 3-nitrotyrosine
  • Tyrosine
  • Creatinine
  • Peroxidase
  • 3-chlorotyrosine