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

Cao,Jiumei; Wu,Qihong; Geng,Liang; Chen,Xiaonan; Shen,Weifeng; Wu,Fang; Chen,Ying

doi:10.3892/mmr.2017.6844

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

Authors:
- Jiumei Cao
- Qihong Wu
- Liang Geng
- Xiaonan Chen
- Weifeng Shen
- Fang Wu
- Ying Chen
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Affiliations: Department of Geratology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China, Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China
Published online on: June 22, 2017 https://doi.org/10.3892/mmr.2017.6844
Pages: 1911-1919
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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1	National Center for Injury Prevention and Control: WISQARS Leading Causes of Death Reports. 1999–2006.
2	Coady MA, Rizzo JA, Goldstein LJ and Elefteriades JA: Natural history, pathogenesis, and etiology of thoracic aortic aneurysms and dissections. Cardiol Clin. 17:615–635. vii:1999. View Article : Google Scholar : PubMed/NCBI
3	El-Hamamsy I and Yacoub MH: Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol. 6:771–786. 2009. View Article : Google Scholar : PubMed/NCBI
4	Barbour JR, Spinale FG and Ikonomidis JS: Proteinase systems and thoracic aortic aneurysm progression. J Surg Res. 139:292–307. 2007. View Article : Google Scholar : PubMed/NCBI
5	Ikonomidis JS, Jones JA, Barbour JR, Stroud RE, Clark LL, Kaplan BS, Zeeshan A, Bavaria JE, Gorman JH III, Spinale FG and Gorman RC: Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with bicuspid or tricuspid aortic valves. J Thorac Cardiovasc Surg. 133:1028–1036. 2007. View Article : Google Scholar : PubMed/NCBI
6	He R, Guo DC, Sun W, Papke CL, Duraisamy S, Estrera AL, Safi HJ, Ahn C, Buja LM, Arnett FC, et al: Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms. J Thorac Cardiovasc Surg. 136:922–929, 929.e1. 2008. View Article : Google Scholar : PubMed/NCBI
7	Zhang X, Shen YH and LeMaire SA: Thoracic aortic dissection: Are matrix metalloproteinases involved? Vascular. 17:147–157. 2009. View Article : Google Scholar : PubMed/NCBI
8	Jones JA, Barbour JR, Lowry AS, Bouges S, Beck C, McClister DM Jr, Mukherjee R and Ikonomidis JS: Spatiotemporal expression and localization of matrix metalloproteinas-9 in a murine model of thoracic aortic aneurysm. J Vasc Surg. 44:1314–1321. 2006. View Article : Google Scholar : PubMed/NCBI
9	Cao J, Geng L, Wu Q, Wang W, Chen Q, Lu L, Shen W and Chen Y: Spatiotemporal expression of matrix metalloproteinases (MMPs) is regulated by the Ca²⁺-signal transducer S100A4 in the pathogenesis of thoracic aortic aneurysm. PLoS One. 8:e700572013. View Article : Google Scholar : PubMed/NCBI
10	Martin KA, Merenick BL, Ding M, Fetalvero KM, Rzucidlo EM, Kozul CD, Brown DJ, Chiu HY, Shyu M, Drapeau BL, et al: Rapamycin promotes vascular smooth muscle cell differentiation through insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt2 feedback signaling. J Biol Chem. 282:36112–36120. 2007. View Article : Google Scholar : PubMed/NCBI
11	Cao J, Gong L, Guo DC, Mietzsch U, Kuang SQ, Kwartler CS, Safi H, Estrera A, Gambello MJ and Milewicz DM: Thoracic aortic disease in tuberous sclerosis complex: Molecular pathogenesis and potential therapies in Tsc2^+/− mice. Hum Mol Genet. 19:1908–1920. 2010. View Article : Google Scholar : PubMed/NCBI
12	Geng L, Wang W, Chen Y, Cao J, Lu L, Chen Q, He R and Shen W: Elevation of ADAM10, ADAM17, MMP-2 and MMP-9 expression with media degeneration features CaCl₂-induced thoracic aortic aneurysm in a rat model. Exp Mol Pathol. 89:72–81. 2010. View Article : Google Scholar : PubMed/NCBI
13	Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, Bourgeois S, Estrera AL, Safi HJ, Sparks E, et al: Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 39:1488–1493. 2007. View Article : Google Scholar : PubMed/NCBI
14	Dodd T, Jadhav R, Wiggins L, Stewart J, Smith E, Russell JC and Rocic P: MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK. J Mol Cell Cardiol. 51:1015–1025. 2011. View Article : Google Scholar : PubMed/NCBI
15	Dabek J, Glogowska-Ligus J and Szadorska B: Transcription activity of MMP-2 and MMP-9 metalloproteinase genes and their tissue inhibitor (TIMP-2) in acute coronary syndrome patients. J Postgrad Med. 59:115–120. 2013. View Article : Google Scholar : PubMed/NCBI
16	Huusko T, Salonurmi T, Taskinen P, Liinamaa J, Juvonen T, Pääkkö P, Savolainen M and Kakko S: Elevated messenger RNA expression and plasma protein levels of osteopontin and matrix metalloproteinase types 2 and 9 in patients with ascending aortic aneurysms. J Thorac Cardiovasc Surg. 145:1117–1123. 2013. View Article : Google Scholar : PubMed/NCBI
17	Nordon IM, Hinchliffe RJ, Loftus IM and Thompson MM: Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol. 8:92–102. 2011. View Article : Google Scholar : PubMed/NCBI
18	Erdheim J: Medionecrosis aortae idiopathica cystica. Virchows Arch (Pathol Anat). 276:187–229. 1930. View Article : Google Scholar
19	Girardi LN and Coselli JS: Inflammatory aneurysm of the ascending aorta and aortic arch. Ann Thorac Surg. 64:251–253. 1997. View Article : Google Scholar : PubMed/NCBI
20	Biddinger A, Rocklin M, Coselli J and Milewicz DM: Familial thoracic aortic dilatations and dissections: A case control study. J Vasc Surg. 25:506–511. 1997. View Article : Google Scholar : PubMed/NCBI
21	Roth M, Lemke P, Bohle RM, Klovekorn WP and Bauer EP: Inflammatory aneurysm of the ascending thoracic aorta. J Thorac Cardiovasc Surg. 123:822–824. 2002. View Article : Google Scholar : PubMed/NCBI
22	He R, Guo DC, Estrera AL, Safi HJ, Huynh TT, Yin Z, Cao SN, Lin J, Kurian T, Buja LM, et al: Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissections. J Thorac Cardiovasc Surg. 131:671–678. 2006. View Article : Google Scholar : PubMed/NCBI
23	Tang PC, Yakimov AO, Teesdale MA, Coady MA, Dardik A, Elefteriades JA and Tellides G: Transmural inflammation by interferon-gamma-producing T cells correlates with outward vascular remodeling and intimal expansion of ascending thoracic aortic aneurysms. FASEB J. 19:1528–1530. 2005.PubMed/NCBI
24	Shepherd J and Nicklin MJ: Elastic-vessel arteritis in interleukin-1 receptor antagonist-deficient mice involves effector Th1 cells and requires interleukin-1 receptor. Circulation. 111:3135–3140. 2005. View Article : Google Scholar : PubMed/NCBI
25	Davis VA, Persidskaia RN, Baca-Regen LM, Fiotti N, Halloran BG and Baxter BT: Cytokine pattern in aneurysmal and occlusive disease of the aorta. J Surg Res. 101:152–156. 2001. View Article : Google Scholar : PubMed/NCBI
26	Jones KG, Brull DJ, Brown LC, Sian M, Greenhalgh RM, Humphries SE and Powell JT: Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms. Circulation. 103:2260–2265. 2001. View Article : Google Scholar : PubMed/NCBI
27	Schönbeck U, Sukhova GK, Gerdes N and Libby P: T(H)2 predominant immune responses prevail in human abdominal aortic aneurysm. Am J Pathol. 161:499–506. 2002. View Article : Google Scholar : PubMed/NCBI
28	Walton LJ, Franklin IJ, Bayston T, Brown LC, Greenhalgh RM, Taylor GW and Powell JT: Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: Implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms. Circulation. 100:48–54. 1999. View Article : Google Scholar : PubMed/NCBI
29	Johnston WF, Salmon M, Pope NH, Meher A, Su G, Stone ML, Lu G, Owens GK, Upchurch GR Jr and Ailawadi G: Inhibition of interleukin-1β decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms. Circulation. 130 11 Suppl 1:51–59. 2014. View Article : Google Scholar : PubMed/NCBI
30	Lesauskaite V, Epistolato MC, Castagnini M, Urbonavicius S and Tanganelli P: Expression of matrix metalloproteinases, their tissue inhibitors, and osteopontin in the wall of thoracic and abdominal aortas with dilatative pathology. Hum Pathol. 37:1076–1084. 2006. View Article : Google Scholar : PubMed/NCBI
31	Boye K and Maelandsmo GM: S100A4 and metastasis: A small actor playing many roles. Am J Pathol. 176:528–535. 2010. View Article : Google Scholar : PubMed/NCBI
32	Senolt L, Grigorian M, Lukanidin E, Simmen B, Michel BA, Pavelka K, Gay RE, Gay S and Neidhart M: S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases. Ann Rheum Dis. 65:1645–1648. 2006. View Article : Google Scholar : PubMed/NCBI
33	Oslejsková L, Grigorian M, Gay S, Neidhart M and Senolt L: The metastasis associated protein S100A4: A potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis. 67:1499–1504. 2008. View Article : Google Scholar : PubMed/NCBI
34	Martin KA, Rzucidlo EM, Merenick BL, Fingar DC, Brown DJ, Wagner RJ and Powell RJ: The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol. 286:C507–C517. 2004. View Article : Google Scholar : PubMed/NCBI
35	Holmes DR Jr, Leon MB, Moses JW, Popma JJ, Cutlip D, Fitzgerald PJ, Brown C, Fischell T, Wong SC, Midei M, et al: Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation. 109:634–640. 2004. View Article : Google Scholar : PubMed/NCBI