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

AbstractBackground n-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. s ated 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. s 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. sion ficiency in bone marrow-derived cells results in larger atherosclerotic lesions, increased lesion-associated Aβ and RAGE, and higher serum cholesterol in male, Ldlr−/− mice.