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S1P 3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species
- フォーマット:
- 論文
- 責任表示:
- Takuwa, Noriko ; Ohkura, Sei-Ichiro ; Takashima, Shin-ichiro ; Ohtani, Keisuke ; Okamoto, Yasuo ; Tanaka, Tamotsu ; Hirano, Kaoru ; Usui, Soichiro ; Wang, Fei ; Du, Wa ; Yoshioka, Kazuaki ; Banno, Yoshiko ; Sasaki, Motoko ; Ichi, Ikuyo ; Okamura, Miwa ; Sugimoto, Naotoshi ; Mizugishi, Kiyomi ; Nakanuma, Yasuni ; Ishii, Isao ; Takamura, Masayuki ; Kaneko, Shuichi ; Kojo, Shosuke ; Satouchi, Kiyoshi ; Mitumori, Kunitoshi ; Chun, Jerold ; Takuwa, Yoh
- 言語:
- 英語
- 出版情報:
- Oxford University Press (OUP), 2010-02-01
- 著者名:
- 掲載情報:
- Cardiovascular Research
- ISSN:
- 0008-6363
- 巻:
- 85
- 通号:
- 3
- 開始ページ:
- 484
- 終了ページ:
- 493
- バージョン:
- author
- 概要:
- 金沢大学医薬保健研究域医学系<br />Aims Sphingosine kinase 1 (SPHK1), its product sphingosine-1-phosphate (S1P), and S1P receptor subtypes have been suggested to play protective roles for cardiomyocytes in animal models of ischaemic preconditioning … and cardiac ischaemia/reperfusion injury. To get more insight into roles for SPHK1 in vivo, we have generated SPHK1-transgenic (TG) mice and analysed the cardiac phenotype.Methods and results SPHK1-TG mice overexpressed SPHK1 in diverse tissues, with a nearly 20-fold increase in enzymatic activity. The TG mice grew normally with normal blood chemistry, cell counts, heart rate, and blood pressure. Unexpectedly, TG mice with high but not low expression levels of SPHK1 developed progressive myocardial degeneration and fibrosis, with upregulation of embryonic genes, elevated RhoA and Rac1 activity, stimulation of Smad3 phosphorylation, and increased levels of oxidative stress markers. Treatment of juvenile TG mice with pitavastatin, an established inhibitor of the Rho family G proteins, or deletion of S1P3, a major myocardial S1P receptor subtype that couples to Rho GTPases and transactivates Smad signalling, both inhibited cardiac fibrosis with concomitant inhibition of SPHK1-dependent Smad-3 phosphorylation. In addition, the anti-oxidant N-2-mercaptopropyonylglycine, which reduces reactive oxygen species (ROS), also inhibited cardiac fibrosis. In in vivo ischaemia/reperfusion injury, the size of myocardial infarct was 30 decreased in SPHK1-TG mice compared with wild-type mice.Conclusion These results suggest that chronic activation of SPHK1-S1P signalling results in both pathological cardiac remodelling through ROS mediated by S1P3 and favourable cardioprotective effects. 続きを見る
- URL:
- http://hdl.handle.net/2297/21766
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Japanese Society of Hypertension 日本高血圧学会 / Nature Publishing Group | |
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American Society for Clinical Investigation | |
日本心臓病学会 = Japanese College of Cardiology / Elsevier | |
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The Physiological Society / Wiley-Blackwell |
BioMed Central Ltd. |