New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis
| Autor: | Shingo Takahara, Sachiko Miyagawa-Tomita, Tetsuya Niihori, Yoko Aoki, Shin Ichi Inoue, Yoshikatsu Saiki, Yoichi Matsubara, Katsuhisa Matsuura, Yasumi Nakashima |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cardiac function curve medicine.medical_specialty Research paper Cardiac fibrosis Cardiomegaly Periostin General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences Adrenergic Agents 0302 clinical medicine Fibrosis Internal medicine medicine Animals Protein kinase B Akt/PKB signaling pathway business.industry Noonan Syndrome Hypertrophic cardiomyopathy General Medicine medicine.disease 030104 developmental biology Endocrinology 030220 oncology & carcinogenesis Mutation ras Proteins Noonan syndrome business |
| Zdroj: | EBioMedicine. 42:43-53 |
| ISSN: | 2352-3964 |
| Popis: | Background: Noonan syndrome (NS) is a genetic disorder characterized by short stature, a distinctive facial appearance, and heart defects. We recently discovered a novel NS gene, RIT1, which is a member of the RAS subfamily of small GTPases. NS patients with RIT1 mutations have a high incidence of hypertrophic cardiomyopathy and edematous phenotype, but the specific role of RIT1 remains unclear. Methods: To investigate how germline RIT1 mutations cause NS, we generated knock-in mice that carried a NS-associated Rit1 A57G mutation (Rit1A57G/＋). We investigated the phenotypes of Rit1A57G/＋ mice in fetal and adult stages as well as the effects of isoproterenol on cardiac function in Rit1A57G/＋ mice. Findings: Rit1A57G/＋ embryos exhibited decreased viability, edema, subcutaneous hemorrhage and AKT activation. Surviving Rit1A57G/＋ mice had a short stature, craniofacial abnormalities and splenomegaly. Cardiac hypertrophy and cardiac fibrosis with increased expression of vimentin and periostin were observed in Rit1A57G/＋ mice compared to Rit1＋/＋ mice. Upon isoproterenol stimulation, cardiac fibrosis was drastically increased in Rit1A57G/＋ mice. Phosphorylated (at Thr308) AKT levels were also elevated in isoproterenol-treated Rit1A57G/＋ hearts. Interpretation: The A57G mutation in Rit1 causes cardiac hypertrophy, fibrosis and other NS19 associated features. Biochemical analysis indicates that the AKT signaling pathway might be related to downstream signaling in the RIT1 A57G mutant at a developmental stage and under β-adrenergic stimulation in the heart. Funding Statement: The Grants-in-Aid were provided by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science KAKENHI Grant. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: All animal experiments were approved by the Animal Care and Use Committee of Tohoku University (2018MdA-090, 2018MdA-022), which conforms NIH guidelines (Guide for the Care and Use of Laboratory Animals, Eighth Edition). |
| Databáze: | OpenAIRE |
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