Glycated Albumin Induces Lipid Infiltration in Mice Aorta Independently of DM and RAS Local Modulation by Inducing Lipid Peroxidation and Inflammation

J Diabetes Complications. Nov-Dec 2016;30(8):1614-1621. doi: 10.1016/j.jdiacomp.2016.07.001. Epub 2016 Jul 5.

Abstract

Aims: Advanced glycated albumin (AGE-albumin) adversely impairs macrophage lipid homeostasis in vitro, which may be prevented by angiotensin receptor blockers. In vivo studies are inconclusive whether AGE-albumin itself plays important role in early-stage atherogenesis. We aimed at investigating how AGE-albumin by itself drives atherosclerosis development in dyslipidemic non-diabetic mice and if its effects are due to the activation of renin-angiotensin system in the arterial wall and the expression of genes and proteins involved in lipid flux.

Methods and results: Murine albumin glycation was induced by incubation with 10mM glycolaldehyde and C-albumin with PBS alone. Twelve-week-old-male apoE knockout mice were submitted to a daily IP injection of control (C) or AGE-albumin (2mg/mL) during 30days with or without losartan (LOS: 100mg/L; C+LOS and AGE+LOS). Aortic arch was removed, and gene expression was determined by RT-PCR and protein content by immunofluorescence. Plasma lipid and glucose levels were similar among groups. Systolic blood pressure was similarly reduced in both groups treated with LOS. In comparison to C-albumin, aortic lipid infiltration was 5.3 times increased by AGE-albumin, which was avoided by LOS. LOS prevented the enhancement induced by AGE-albumin in Ager, Tnf and Cybb mRNA levels but did not reduce Olr1. Nfkb and Agt mRNA levels were unchanged by AGE-albumin. LOS similarly reduced Agtr1a mRNA level in both C and AGE-albumin groups. In AGE-albumin-treated mice, immunofluorescence for carboxymethyl-lysine, 4-hydroxynonenal and RAGE was respectively, 4.8, 2.6 and 1.7 times enhanced in comparison to C-albumin. These increases were all avoided by LOS.

Conclusions: AGE-albumin evokes a pre-stage of atherogenesis in dyslipidemic mice independently of the presence of diabetes mellitus or modulation in the RAS in part by the induction of lipid peroxidation and inflammation.

Keywords: Advanced glycation; Atherosclerosis; Glycated albumin; Inflammation; Losartan; Oxidative stress.

MeSH terms

  • Animals
  • Aorta / pathology*
  • Atherosclerosis / physiopathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Dyslipidemias / physiopathology*
  • Inflammation / pathology*
  • Lipid Peroxidation*
  • Lipids
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Renin-Angiotensin System
  • Serum Albumin / administration & dosage*

Substances

  • Lipids
  • Serum Albumin
  • glycosylated serum albumin