ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome
ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome
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DOI：
10.1016/j.cmet.2006.10.002
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发表时间：
2006-11-01
期刊：
影响因子：
29
通讯作者：
Semenkovich, Clay F.
中科院分区：
文献类型：
--
作者：
Schneider, Jochen G.;Finck, Brian N.;Semenkovich, Clay F.
代谢综合征与胰岛素抵抗和动脉粥样硬化有关。在这里，我们发现，ATM（一种在易患癌症的共济失调毛细血管扩张症中突变的蛋白质）的一个或两个等位基因的缺陷，会恶化 apoE(-/-) 小鼠的代谢综合征特征，增加胰岛素抵抗，并加速动脉粥样硬化。与ATM(+/+)骨髓移植相比，ATM(-/-)骨髓移植增加了血管疾病。 ATM 缺陷细胞中 Jun N 末端激酶 (JNK) 活性增加。用低剂量氯喹（一种 ATM 激活剂）治疗 ATM(+/+)apoE(-/-) 小鼠，可减少动脉粥样硬化。氯喹以 ATM 依赖性方式降低巨噬细胞 JNK 活性、降低巨噬细胞脂蛋白脂肪酶活性（JNK 激活的促动脉粥样硬化后果）、降低血压并改善葡萄糖耐量。氯喹还改善了 ob/ob 和 db/db 小鼠的代谢异常。这些结果表明，ATM 依赖性应激途径介导对代谢综合征的易感性，并且促进 ATM 活性的氯喹或相关药物可以调节胰岛素抵抗并减少血管疾病。
Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE(-/-) mice. Transplantation with ATM(-/-) as compared to ATM(+/+) bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM(+/+)apoE(-/-) mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATMdependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.