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

Takuwa, Noriko; Ohkura, Sei Ichiro; Takashima, S; Ohtani, Kazuhiro; Okamoto, Yasuo; Tanaka, Tamotsu; Hirano, Katsuhiko; 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

doi:10.1093/cvr/cvp312

Cited by 136 publications

(113 citation statements)

References 30 publications

(48 reference statements)

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…In contrast, mice with germ line ablation of the Sgpp1 gene, which encodes the degrading enzyme S1P phosphatase 1 (Allende et al, 2013) and mice with forced over-expression SphK1 via an Sphk1 transgene driven by a broad spectrum promoter (Takuwa et al, 2010) do not have differences in circulating S1P (plasma) as compared with wildtype control mice. However, mice lacking the S1P-degrading enzyme S1P lyase (via germ line ablation of Sgpl1) have serum S1P levels that are 4-fold higher than wild-type littermates (Bektas et al, 2010).…”

Section: Discussionmentioning

confidence: 98%

Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Kharel

Morris²,

Congdon³

et al. 2015

J Pharmacol Exp Ther

106

View full text Add to dashboard Cite

Sphingosine 1-phosphate (S1P) levels are significantly higher in blood and lymph than in tissues. This S1P concentration difference is necessary for proper lymphocyte egress from secondary lymphoid tissue and to maintain endothelial barrier integrity. Studies with mice lacking either sphingosine kinase (SphK) type 1 and 2 indicate that these enzymes are the sole biosynthetic source of S1P, but they play different roles in setting S1P blood levels. We have developed a set of drug-like SphK inhibitors, with differing selectivity for the two isoforms of this enzyme. Although all SphK inhibitors tested decrease S1P when applied to cultured U937 cells, only those inhibitors with a bias for SphK2 drove a substantial increase in blood S1P in mice and this rise was detectable within minutes of administration of the inhibitor. Blood S1P also increased in response to SphK2 inhibitors in rats. Mass-labeled S1P was cleared more slowly after intravenous injection into SphK2 inhibitortreated mice or mice lacking a functional SphK2 gene; thus, the increased accumulation of S1P in the blood appears to result from the decreased clearance of S1P from the blood. Therefore, SphK2 appears to have a function independent of generating S1P in cells. Our results suggest that differential SphK inhibition with a drug might afford a method to manipulate blood S1P levels in either direction while lowering tissue S1P levels.

show abstract

Section: Discussionmentioning

confidence: 98%

Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels

Kharel

Morris²,

Congdon³

et al. 2015

J Pharmacol Exp Ther

106

View full text Add to dashboard Cite

show abstract

“…In physiologic conditions, MABP was not altered by the loss of Sphk1 2/2 or Sphk2 2/2 (Furuya et al, 2013;Gorshkova et al, 2013), or the overexpression of SPHK1 (Takuwa et al, 2010). In a model of histamine-induced hypotension, Olivera et al (2010) showed that Sphk1 2/2 mice, but not Sphk2 2/2 mice, were significantly more hypotensive than WT mice.…”

Section: S1p: New Player In Bp Regulation?mentioning

confidence: 93%

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

Cantalupo

Lorenzo

2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Initially discovered as abundant components of eukaryotic cell membranes, sphingolipids are now recognized as important bioactive signaling molecules that modulate a variety of cellular functions, including those relevant to cancer and immunologic, inflammatory, and cardiovascular disorders. In this review, we discuss recent advances in our understanding of the role of sphingosine-1-phosphate (S1P) receptors in the regulation of vascular function, and focus on how de novo biosynthesized sphingolipids play a role in blood pressure homeostasis. The therapeutic potential of new drugs that target S1P signaling is also discussed.

show abstract

“…A clear role for S1P 3 has also been demonstrated in the regulation of heart rate in rodents (Forrest et al, 2004;Sanna et al, 2004), and it has been shown to regulate lymphoid endothelial cells (Girkontaite et al, 2004) and to have effects on endothelial progenitor cells (Walter et al, 2007). S1P 3 regulates myocardial perfusion and provides protection in ischemia-reperfusion injury (Levkau et al, 2004;Theilmeier et al, 2006;Means et al, 2007) and further influences vasorelaxation (Nofer et al, 2004) and cardiac fibrosis (Takuwa et al, 2009). Other influences on myofibroblasts (Keller et al, 2007), as well as S1P 3 links to PAR-1 signaling that couples coagulation events with inflammation (Niessen et al, 2008), have been reported.…”

Section: B Sphingosine 1-phosphate Receptorsmentioning

confidence: 99%