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

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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.


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-RapKO mice) into Ldlr−/− mice and then fed them the Western-type diet. Atherosclerotic lesions from Mac-RapKO 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-RapKO macrophages. Although wild-type and Mac-RapKO macrophages showed similar STAT3 phosphorylation on Tyr705, Mac-RapKO macrophages showed decreased STAT3Ser727 phosphorylation in response to minimally modified low-density lipoprotein treatment and decreased Ccl2 promoter binding of STAT3.


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.

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