Insulin-degrading enzyme deficiency in bone marrow cells increases atherosclerosis in LDL receptor-deficient mice

Cardiovasc Pathol. 2013 Nov-Dec;22(6):458-64. doi: 10.1016/j.carpath.2013.03.006. Epub 2013 May 17.

Abstract

Background: Insulin-degrading enzyme (IDE), a protease implicated in several chronic diseases, associates with the cytoplasmic domain of the macrophage Type A scavenger receptor (SR-A). Our goal was to investigate the effect of IDE deficiency (Ide(-/-)) on diet-induced atherosclerosis in low density lipoprotein-deficient (Ldlr(-/-)) mice and on SR-A function.

Methods: Irradiated Ldlr(-/-) or Ide(-/-)Ldlr(-/-) mice were reconstituted with wild-type or Ide(-/-) bone marrow and, 6 weeks later, were placed on a high-fat diet for 8 weeks.

Results: After 8 weeks on a high-fat diet, male Ldlr(-/-) recipients of Ide(-/-) bone marrow had more atherosclerosis, higher serum cholesterol and increased lesion-associated β-amyloid, an IDE substrate, and receptor for advanced glycation end products (RAGE), a proinflammatory receptor for β-amyloid, compared to male Ldlr(-/-) recipients of wild-type bone marrow. IDE deficiency in male Ldlr(-/-) recipient mice did not affect atherosclerosis or cholesterol levels and moderated the effects of IDE deficiency of bone marrow-derived cells. No differences were seen between Ldlr(-/-) and Ide(-/-)Ldlr(-/-) female mice reconstituted with Ide(-/-) or wild-type bone marrow. IDE deficiency in macrophages did not alter SR-A levels, cell surface SR-A, or foam cell formation.

Conclusion: IDE deficiency in bone marrow-derived cells results in larger atherosclerotic lesions, increased lesion-associated Aβ and RAGE, and higher serum cholesterol in male, Ldlr(-/-) mice.

Keywords: Amyloid; Atherosclerosis; Bone marrow transplantation; Insulin-degrading enzyme; LDL receptor-deficient mice; Receptor for advanced glycation end products (RAGE).

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aortic Diseases / blood
  • Aortic Diseases / enzymology*
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Atherosclerosis / blood
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Bone Marrow Cells / enzymology*
  • Bone Marrow Transplantation
  • Cholesterol / blood
  • Diet, High-Fat
  • Disease Models, Animal
  • Female
  • Foam Cells / enzymology
  • Insulysin / deficiency*
  • Insulysin / genetics
  • Lipoproteins, LDL / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Scavenger Receptors, Class A / metabolism
  • Sex Factors
  • Time Factors

Substances

  • Amyloid beta-Peptides
  • Lipoproteins, LDL
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Receptors, LDL
  • Scavenger Receptors, Class A
  • acetyl-LDL
  • Cholesterol
  • Insulysin