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

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 beta-amyloid, an IDE substrate, and receptor for advanced glycation end products (RAGE), a proinflammatory receptor for beta-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 A beta and RAGE, and higher serum cholesterol in male, Ldlr(-/-) mice. (C) 2013 Elsevier Inc. All rights reserved.