Han Seongah, Liang Chien-Ping, DeVries-Seimon Tracie, Ranalletta Mollie, Welch Carrie L, Collins-Fletcher Kadesha, Accili Domenico, Tabas Ira, Tall Alan R
Department of Medicine, Columbia University, New York, New York 10032, USA.
Cell Metab. 2006 Apr;3(4):257-66. doi: 10.1016/j.cmet.2006.02.008.
Insulin resistance in diabetes and metabolic syndrome is thought to increase susceptibility to atherosclerotic cardiovascular disease, but the underlying mechanisms are poorly understood. To evaluate the possibility that decreased insulin signaling in macrophage foam cells might worsen atherosclerosis, Ldlr(-/-) mice were transplanted with insulin receptor Insr(+/+) or Insr(-/-) bone marrow. Western diet-fed Insr(-/-) recipients developed larger, more complex lesions with increased necrotic cores and increased numbers of apoptotic cells. Insr(-/-) macrophages showed diminished Akt phosphorylation and an augmented ER stress response, leading to induction of scavenger receptor A and increased apoptosis when challenged with cholesterol loading or nutrient deprivation. These studies suggest that defective insulin signaling and reduced Akt activity impair the ability of macrophages to deal with ER stress-induced apoptosis within atherosclerotic plaques.
糖尿病和代谢综合征中的胰岛素抵抗被认为会增加动脉粥样硬化性心血管疾病的易感性，但其潜在机制尚不清楚。为了评估巨噬细胞泡沫细胞中胰岛素信号减少可能会加重动脉粥样硬化的可能性，将胰岛素受体Insr(+/+)或Insr(-/-)骨髓移植到Ldlr(-/-)小鼠体内。用西方饮食喂养的Insr(-/-)受体形成了更大、更复杂的病变，坏死核心增加，凋亡细胞数量增多。Insr(-/-)巨噬细胞显示Akt磷酸化减少和内质网应激反应增强，在受到胆固醇负荷或营养剥夺刺激时，导致清道夫受体A的诱导和凋亡增加。这些研究表明，胰岛素信号缺陷和Akt活性降低损害了巨噬细胞处理动脉粥样硬化斑块内内质网应激诱导的凋亡的能力。
