Journal Article

Therapeutic Effect of Rapamycin on Aortic Dissection in Mice

Majima, Ryohei, Ito, Sohei, Aoki, Hiroki, Fukumoto, Yoshihiro, Hirakata, Saki, Furusho, Aya, Ohno-Urabe, Satoko, Nishida, Norifumi, Matsukuma, Miho, Hashimoto, Yohei, Hayashi-Hori, Makiko

2020

Overview

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 β-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.

• Publisher: MDPI AG,MDPI
• Subject: Aminopropionitrile - toxicity / Aneurysm, Dissecting - chemically induced / Aneurysm, Dissecting - drug therapy / Aneurysm, Dissecting - metabolism / Aneurysm, Dissecting - prevention & control / Angiotensin II - toxicity / Animals / Aortic dissection / Cell cycle / Cell Cycle Checkpoints - drug effects / Cell Cycle Checkpoints - genetics / Cell Line / Coronary vessels / Disease Models, Animal / Gefitinib - pharmacology / Gefitinib - therapeutic use / Gene expression / Gene Expression Regulation - drug effects / Gene Ontology / Gene Regulatory Networks - drug effects / Genotype & phenotype / Growth factors / Inhibitor drugs / Kinases / Male / Metabolism / Mice / Mortality / Muscle, Smooth, Vascular - drug effects / Muscle, Smooth, Vascular - metabolism / Pathogenesis / Proto-Oncogene Proteins c-akt - metabolism / Signal Transduction - drug effects / Sirolimus - pharmacology / Sirolimus - therapeutic use / Smooth muscle / STAT3 Transcription Factor - metabolism / TOR Serine-Threonine Kinases - metabolism