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Molecular medicine reports

Rapamycin inhibits CaCl2-induced thoracic aortic aneurysm formation in rats through mTOR-mediated suppression of proinflammatory mediators.


PMID 28656223

Abstract

The aim of the present study was to investigate the effect of the mammalian target of rapamycin (mTOR) signaling pathway on thoracic aortic aneurysm (TAA) development. The study used a calcium chloride (CaCl2)‑induced rat TAA model to explore the potential role of mTOR signaling pathway in the disease development. Adult male Sprague‑Dawley rats underwent the periarterial exposure of thoracic aorta to either 0.5 M CaCl2 or normal saline, and a subgroup of CaCl2‑treated rats received rapamycin 1 day prior to surgery. Without pre‑administering rapamycin, significantly enhanced phosphorylation of mTOR and expression of proinflammatory cytokines [i.e., tumor necrosis factor α (TNF‑α), interleukin 6 (IL‑6), and interleukin (IL)‑1β] were observed in the CaCl2‑treated aortic segments 2 days post‑treatment compared with the NaCl‑treated segments. At 2 weeks post‑treatment, hematoxylin and eosin and Verhoeff‑Van Gieson staining revealed aneurysmal alteration and disappearance of normal wavy elastic structures in the aortic segments exposed to CaCl2. In contrast, the CaCl2‑induced TAA formation was inhibited by pre‑administering rapamycin to CaCl2‑treated rats, which demonstrated attenuated mTOR phosphorylation and downregulation of the proinflammatory mediators (i.e., TNF‑α, IL‑6, IL‑1β, matrix metallopeptidases 2 and 9) to the control level. Further in vitro cell culture experiments using aortic smooth muscle cell (SMC) suggested that the inhibition of the mTOR signaling pathway by rapamycin could promote the differentiation of SMCs, as reflected by the reduced expression of S100A4 and osteopontin. The present study indicated that the early enhanced mTOR signaling pathway in the TAA development and mTOR inhibitor rapamycin may inhibit CaCl2‑induced TAA formation.