Disruption of Mammalian Target of Rapamycin Complex 1 in Macrophages Decreases Chemokine Gene Expression and Atherosclerosis

作者：Ai, Ding^*; Jiang, Hongfeng; Westerterp, Marit; Murphy, Andrew J.; Wang, Mi; Ganda, Anjali; Abramowicz, Sandra; Welch, Carrie; Almazan, Felicidad; Zhu, Yi; Miller, Yury I.; Tall, Alan R.

来源：Circulation Research, 2014, 114(10): 1576-1584.

DOI：10.1161/CIRCRESAHA.114.302313

• atherosclerosis
• macrophages
• mammalian target of rapamycin complex 1

Rationale: The mammalian target of rapamycin complex 1 inhibitor, rapamycin, has been shown to decrease atherosclerosis, even while increasing plasma low-density lipoprotein levels. This suggests an antiatherogenic effect possibly mediated by the modulation of inflammatory responses in atherosclerotic plaques. @@@ Objective: Our aim was to assess the role of macrophage mammalian target of rapamycin complex 1 in atherogenesis. @@@ Methods and Results: We transplanted bone marrow from mice in which a key mammalian target of rapamycin complex 1 adaptor, regulatory-associated protein of mTOR, was deleted in macrophages by Cre/loxP recombination (Mac-Rap(KO) mice) into Ldlr(-/-) mice and then fed them the Western-type diet. Atherosclerotic lesions from Mac-Rap(KO) mice showed decreased infiltration of macrophages, lesion size, and chemokine gene expression compared with control mice. Treatment of macrophages with minimally modified low-density lipoprotein resulted in increased levels of chemokine mRNAs and signal transducer and activator of transcription (STAT) 3 phosphorylation; these effects were reduced in Mac-Rap(KO) macrophages. Although wild-type and Mac-Rap(KO) macrophages showed similar STAT3 phosphorylation on Tyr705, Mac-Rap(KO) macrophages showed decreased STAT3Ser727 phosphorylation in response to minimally modified low-density lipoprotein treatment and decreased Ccl2 promoter binding of STAT3. @@@ Conclusions: The results demonstrate cross-talk between nutritionally induced mammalian target of rapamycin complex 1 signaling and minimally modified low-density lipoprotein-mediated inflammatory signaling via combinatorial phosphorylation of STAT3 in macrophages, leading to increased STAT3 activity on the chemokine (C-C motif) ligand 2 (monocyte chemoattractant protein 1) promoter with proatherogenic consequences.

• 出版日期2014-5-9
• 单位天津医科大学