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Therapeutic Effect of Rapamycin on Aortic Dissection in Mice.

ABSTRACT: 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 ?-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.

SUBMITTER: Hayashi-Hori M

PROVIDER: S-EPMC7246910 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Therapeutic Effect of Rapamycin on Aortic Dissection in Mice.

Hayashi-Hori Makiko M Aoki Hiroki H Matsukuma Miho M Majima Ryohei R Hashimoto Yohei Y Ito Sohei S Hirakata Saki S Nishida Norifumi N Furusho Aya A Ohno-Urabe Satoko S Fukumoto Yoshihiro Y

International journal of molecular sciences 20200508 9

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 da ...[more]

PMID: 32397282

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Project description:ImportanceFluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD.ObjectiveTo examine the effect of ciprofloxacin on AAD development in mice.Design, setting, and participantsIn a mouse model of moderate, sporadic AAD, 4-week-old male and female C57BL/6J mice were challenged with a high-fat diet and low-dose angiotensin infusion (1000 ng/min/kg). Control unchallenged mice were fed a normal diet and infused with saline. After randomization, challenged and unchallenged mice received ciprofloxacin (100 mg/kg/d) or vehicle through daily gavage during angiotensin or saline infusion. Aortic aneurysm and dissection development and aortic destruction were compared between mice. The direct effects of ciprofloxacin on aortic smooth muscle cells were examined in cultured cells.ResultsNo notable aortic destruction was observed in unchallenged mice that received ciprofloxacin alone. Aortic challenge induced moderate aortic destruction with development of AAD in 17 of 38 mice (45%) and severe AAD in 9 (24%) but no rupture or death. However, challenged mice that received ciprofloxacin had severe aortic destruction and a significantly increased incidence of AAD (38 of 48 [79%]; P = .001; χ2 = 10.9), severe AAD (32 of 48 [67%]; P < .001; χ2 = 15.7), and rupture and premature death (7 of 48 [15%]; P = .01; χ2 = 6.0). The increased AAD incidence was observed in different aortic segments and was similar between male and female mice. Compared with aortic tissues from challenged control mice, those from challenged mice that received ciprofloxacin showed decreased expression of lysyl oxidase, an enzyme that is critical in the assembly and stabilization of elastic fibers and collagen. These aortas also showed increased matrix metalloproteinase levels and activity, elastic fiber fragmentation, and aortic cell injury. In cultured smooth muscle cells, ciprofloxacin treatment significantly reduced lysyl oxidase expression and activity, increased matrix metalloproteinase expression and activity, suppressed cell proliferation, and induced cell death. Furthermore, ciprofloxacin-a DNA topoisomerase inhibitor-caused nuclear and mitochondrial DNA damage and the release of DNA into the cytosol, subsequently inducing mitochondrial dysfunction, reactive oxygen species production, and activation of the cytosolic DNA sensor STING, which we further showed was involved in the suppression of lysyl oxidase expression and induction of matrix metalloproteinase expression.Conclusions and relevanceCiprofloxacin increases susceptibility to aortic dissection and rupture in a mouse model of moderate, sporadic AAD. Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for AAD.

Project description:Acute aortic dissection (AAD) is one of the major aortic diseases that occurs without a preceding symptom and often results in sudden death. Despite the recent advances in cardiovascular medicine, AAD remains a serious problem because its molecular pathogenesis is largely unknown. In this paper, we report our serendipitous discovery that stress-induced expression of tenascin C (TNC), a member of matricellular proteins, is the protection mechanism of aorta to prevent AAD. The aortic wall stress imposed by the aortic stiffening and the angiotensin II infusion caused the strong induction of TNC in wild type mouse aorta without gross morphological changes. While TNC knockout mice at the baseline showed no morphological, histological or biomechanical abnormalities of aorta, deletion of TNC gene rendered the aorta susceptible to AAD upon the aortic stress. The stressed TNC-null aorta showed the loss of the tensile strength due to the insufficient expression of extracellular matrix proteins and the exaggerated proinflammatory response before the onset of AAD. Therefore, TNC works as a stress-activated molecular damper both by reinforcing the tensile strength and by limiting the excessive proinflammatory response in aorta. Thus far, the molecular event that leads to the AAD development has been unclear because of the unpredictable nature of the AAD onset. This study sheds light on the previously unrecognized tissue protection mechanism that converts the potentially harmful stress response into the active reinforcement of the aorta, of which failure leads to the development of AAD. Although TNC is expressed in various tissues upon the mechanical and proinflammatory stimuli, its role has long been a mystery. Our data uncovered the adaptive role of TNC in aorta that must be resilient to the continuous hemodynamic and humoral stress for lifetime. We used periaortic application of 0.5 M CaCl2 to the infrarenal aorta or either wild type (WT) or tenascin C knockout (TNC-KO) mice to create the mouse model for stiffened aorta and infused the mice with AngII (1 µg/min/kg) for 1 week to apply the pathological stress on aorta (Ca+AngII). Mice were then killed with an overdose of pentobarbital to obtain the tissue samples. The suprarenal aortic samples, from the level of right renal artery to 10 mm above the right renal artery, and infrarenal aortic samples, from the level of left renal artery to 10 mm below the left renal artery, were collected and kept in RNAlater (Qiagen) until the extraction of total RNA using RNeasy (Qiagen). We obtained the RNA samples from 8 mice with Ca+AngII treatment and 5 mice without Ca+AngII treatment for each genotype. We pooled the RNA samples with the identical experimental condition to perform the transcriptome analysis using Mouse Genome 430 2.0 (Affymetrix). We obtained suprarenal aortic smooth muscle cells (ASMCs) from TNC-KO mice by enzymatic dispersion and cultured them in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum. We cultured TNC-KO ASMCs in the presence or absence of exogenous TNC (10 µg/mL) and stimulated the cells with 10 ng/mL TNF-alpha for 24 h before obtaining total RNA using RNeasy. We used 3 independent ASMC cultures without the exogenous TNC and 4 independent cultures with the exogenous TNC. We hybridized each of the RNA samples individually to Mouse Genome 430 2.0 Array (Affymetrix).

Dataset Information

Therapeutic Effect of Rapamycin on Aortic Dissection in Mice.

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Therapeutic Effect of Rapamycin on Aortic Dissection in Mice.

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