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Cardiovascular Research Advance Access first published online on September 15, 2009
This version [Corrected Proof] published online on October 6, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp312
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species

Noriko Takuwa1,2, Sei-Ichiro Ohkura1,3, Shin-Ichiro Takashima1,3, Keisuke Ohtani3, Yasuo Okamoto1, Tamotsu Tanaka4, Kaoru Hirano4, Soichiro Usui3, Fei Wang1, Wa Du1, Kazuaki Yoshioka1, Yoshiko Banno5, Motoko Sasaki6, Ikuyo Ichi7, Miwa Okamura8, Naotoshi Sugimoto1, Kiyomi Mizugishi1, Yasuni Nakanuma6, Isao Ishii9, Masayuki Takamura3, Shuichi Kaneko3, Shosuke Kojo7, Kiyoshi Satouchi4, Kunitoshi Mitumori8, Jerold Chun10 and Yoh Takuwa1,*

1 Department of Physiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan
2 Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, Kahoku, Ishikawa 929-1212, Japan
3 Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa 920-8640, Japan
4 Department of Applied Biological Science, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
5 Department of Cell Signaling, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
6 Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa 920-8640, Japan
7 Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
8 Department of Veterinary Medicine, Tokyo University of Agricultural Technology, Fuchu 183-8509, Tokyo, Japan
9 Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
10 Department of Molecular Biology, The Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA 92037, USA

* Corresponding author. Tel: +81 76 265 2165, Fax: +81 76 234 4223, Email: ytakuwa{at}med.kanazawa-u.ac.jp

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.

KEYWORDS Sphingosine kinase-1 transgenic mouse; Cardiac fibrosis; Ischemia/reperfusion injury; S1P3; Reactive oxygen species

Time for primary review: 23 days


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