PMID- 32397282 OWN - NLM STAT- MEDLINE DCOM- 20210304 LR - 20221207 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 21 IP - 9 DP - 2020 May 8 TI - Therapeutic Effect of Rapamycin on Aortic Dissection in Mice. LID - 10.3390/ijms21093341 [doi] LID - 3341 AB - Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of beta-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis. FAU - Hayashi-Hori, Makiko AU - Hayashi-Hori M AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Aoki, Hiroki AU - Aoki H AD - Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka 830-0011, Japan. FAU - Matsukuma, Miho AU - Matsukuma M AD - Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Majima, Ryohei AU - Majima R AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Hashimoto, Yohei AU - Hashimoto Y AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Ito, Sohei AU - Ito S AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Hirakata, Saki AU - Hirakata S AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Nishida, Norifumi AU - Nishida N AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Furusho, Aya AU - Furusho A AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Ohno-Urabe, Satoko AU - Ohno-Urabe S AUID- ORCID: 0000-0002-4180-2857 AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. FAU - Fukumoto, Yoshihiro AU - Fukumoto Y AD - Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan. LA - eng GR - 16K19434, 19K09280, 21390367, 24390334, 24659640, 26670621, 16H05428, 19H03743/Japan Society for the Promotion of Science/ GR - N/A/Daiichi Sankyo Foundation of Life Science/ GR - N/A/Uehara Memorial Foundation/ GR - N/A/Vehicle Racing Commemorative Foundation/ GR - N/A/TaNeDS/ GR - N/A/Bristol-Myers Squibb/ PT - Journal Article DEP - 20200508 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 11128-99-7 (Angiotensin II) RN - 151-18-8 (Aminopropionitrile) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Akt2 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - S65743JHBS (Gefitinib) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Aminopropionitrile/toxicity MH - Aortic Dissection/chemically induced/*drug therapy/*metabolism/prevention & control MH - Angiotensin II/toxicity MH - Animals MH - Cell Cycle Checkpoints/*drug effects/genetics MH - Cell Line MH - Disease Models, Animal MH - Gefitinib/pharmacology/therapeutic use MH - Gene Expression Regulation/*drug effects MH - Gene Ontology MH - Gene Regulatory Networks/*drug effects MH - Male MH - Mice MH - Muscle, Smooth, Vascular/*drug effects/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - STAT3 Transcription Factor/metabolism MH - Signal Transduction/drug effects MH - Sirolimus/*pharmacology/therapeutic use MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC7246910 OTO - NOTNLM OT - aortic dissection OT - inflammation OT - mTOR OT - rapamycin OT - smooth muscle cells COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. EDAT- 2020/05/14 06:00 MHDA- 2021/03/05 06:00 PMCR- 2020/05/01 CRDT- 2020/05/14 06:00 PHST- 2020/04/16 00:00 [received] PHST- 2020/05/05 00:00 [revised] PHST- 2020/05/06 00:00 [accepted] PHST- 2020/05/14 06:00 [entrez] PHST- 2020/05/14 06:00 [pubmed] PHST- 2021/03/05 06:00 [medline] PHST- 2020/05/01 00:00 [pmc-release] AID - ijms21093341 [pii] AID - ijms-21-03341 [pii] AID - 10.3390/ijms21093341 [doi] PST - epublish SO - Int J Mol Sci. 2020 May 8;21(9):3341. doi: 10.3390/ijms21093341.