S1P 3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species

Noriko Takuwa, Sei Ichiro Ohkura, Shin Ichiro Takashima, Keisuke Ohtani, Yasuo Okamoto, Tamotsu Tanaka, Kaoru Hirano, Soichiro Usui, Fei Wang, Wa Du, Kazuaki Yoshioka, Yoshiko Banno, Motoko Sasaki, Ikuyo Ichi, Miwa Okamura, Naotoshi Sugimoto, Kiyomi Mizugishi, Yasuni Nakanuma, Isao Ishii, Masayuki TakamuraShuichi Kaneko, Shosuke Kojo, Kiyoshi Satouchi, Kunitoshi Mitumori, Jerold Chun, Yoh Takuwa

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)484-493
Number of pages10
JournalCardiovascular Research
Volume85
Issue number3
DOIs
Publication statusPublished - 2010 Feb
Externally publishedYes

Fingerprint

Transgenic Mice
Reactive Oxygen Species
Fibrosis
Lysosphingolipid Receptors
rho GTP-Binding Proteins
Reperfusion Injury
Phosphorylation
sphingosine 1-phosphate
sphingosine kinase
Ischemic Preconditioning
Blood Cell Count
Cardiac Myocytes
Oxidants
Oxidative Stress
Up-Regulation
Animal Models
Heart Rate
Myocardial Infarction
Blood Pressure
Phenotype

Keywords

  • Cardiac fibrosis
  • Ischemia/reperfusion injury
  • Reactive oxygen species
  • S1P 3
  • Sphingosine kinase-1 transgenic mouse

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Takuwa, N., Ohkura, S. I., Takashima, S. I., Ohtani, K., Okamoto, Y., Tanaka, T., ... Takuwa, Y. (2010). S1P 3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. Cardiovascular Research, 85(3), 484-493. https://doi.org/10.1093/cvr/cvp312

S1P 3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. / 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.

In: Cardiovascular Research, Vol. 85, No. 3, 02.2010, p. 484-493.

Research output: Contribution to journalArticle

Takuwa, N, Ohkura, SI, Takashima, SI, Ohtani, K, Okamoto, Y, Tanaka, T, Hirano, K, Usui, S, Wang, F, Du, W, Yoshioka, K, Banno, Y, Sasaki, M, Ichi, I, Okamura, M, Sugimoto, N, Mizugishi, K, Nakanuma, Y, Ishii, I, Takamura, M, Kaneko, S, Kojo, S, Satouchi, K, Mitumori, K, Chun, J & Takuwa, Y 2010, 'S1P 3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species', Cardiovascular Research, vol. 85, no. 3, pp. 484-493. https://doi.org/10.1093/cvr/cvp312
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. / S1P 3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. In: Cardiovascular Research. 2010 ; Vol. 85, No. 3. pp. 484-493.
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T1 - S1P 3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species

AU - Takuwa, Noriko

AU - Ohkura, Sei Ichiro

AU - Takashima, Shin Ichiro

AU - Ohtani, Keisuke

AU - Okamoto, Yasuo

AU - Tanaka, Tamotsu

AU - Hirano, Kaoru

AU - Usui, Soichiro

AU - Wang, Fei

AU - Du, Wa

AU - Yoshioka, Kazuaki

AU - Banno, Yoshiko

AU - Sasaki, Motoko

AU - Ichi, Ikuyo

AU - Okamura, Miwa

AU - Sugimoto, Naotoshi

AU - Mizugishi, Kiyomi

AU - Nakanuma, Yasuni

AU - Ishii, Isao

AU - Takamura, Masayuki

AU - Kaneko, Shuichi

AU - Kojo, Shosuke

AU - Satouchi, Kiyoshi

AU - Mitumori, Kunitoshi

AU - Chun, Jerold

AU - Takuwa, Yoh

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KW - Cardiac fibrosis

KW - Ischemia/reperfusion injury

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KW - Sphingosine kinase-1 transgenic mouse

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