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 language | English |
|---|---|
| Pages (from-to) | 484-493 |
| Number of pages | 10 |
| Journal | Cardiovascular Research |
| Volume | 85 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2010 Feb |
| Externally published | Yes |
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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
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 journal › Article
}
TY - JOUR
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
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Cardiac fibrosis
KW - Ischemia/reperfusion injury
KW - Reactive oxygen species
KW - S1P 3
KW - Sphingosine kinase-1 transgenic mouse
UR - http://www.scopus.com/inward/record.url?scp=74249083210&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=74249083210&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvp312
DO - 10.1093/cvr/cvp312
M3 - Article
C2 - 19755413
AN - SCOPUS:74249083210
VL - 85
SP - 484
EP - 493
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 3
ER -