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Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells.

Publication ,  Journal Article
Estrada, R; Zeng, Q; Lu, H; Sarojini, H; Lee, J-F; Mathis, SP; Sanchez, T; Wang, E; Kontos, CD; Lin, C-Y; Hla, T; Haribabu, B; Lee, M-J
Published in: J Biol Chem
October 31, 2008

Vascular endothelial cells (ECs) have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest state called "cellular senescence." It has been shown that sphingolipids may be involved in senescence; however, the molecular links involved are poorly understood. In this study, we investigated the signaling and functions of sphingosine 1-phosphate (S1P), a serum-borne bioactive sphingolipid, in ECs of different in vitro ages. We observed that S1P-regulated responses are significantly inhibited and the S1P(1-3) receptor subtypes are markedly increased in senescent ECs. Increased expression of S1P(1) and S1P(2) was also observed in the lesion regions of atherosclerotic endothelium, where senescent ECs have been identified in vivo. S1P-induced Akt and ERK1/2 activation were comparable between ECs of different in vitro ages; however, PTEN (phosphatase and tensin homolog deleted on chromosome 10) activity was significantly elevated and Rac activation was inhibited in senescent ECs. Rac activation and senescent-associated impairments were restored in senescent ECs by the expression of dominant-negative PTEN and by knocking down S1P(2) receptors. Furthermore, the senescent-associated impairments were induced in young ECs by the expression of S1P(2) to a level similar to that of in vitro senescence. These results indicate that the impairment of function in senescent ECs in culture is mediated by an increase in S1P signaling through S1P(2)-mediated activation of the lipid phosphatase PTEN.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

October 31, 2008

Volume

283

Issue

44

Start / End Page

30363 / 30375

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Receptors, Lysosphingolipid
  • PTEN Phosphohydrolase
  • Models, Biological
  • Humans
  • Genes, Dominant
  • Endothelial Cells
  • Chemotaxis
  • Cellular Senescence
 

Citation

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Estrada, R., Zeng, Q., Lu, H., Sarojini, H., Lee, J.-F., Mathis, S. P., … Lee, M.-J. (2008). Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells. J Biol Chem, 283(44), 30363–30375. https://doi.org/10.1074/jbc.M804392200
Estrada, Rosendo, Qun Zeng, Hongwei Lu, Harshini Sarojini, Jen-Fu Lee, Steven P. Mathis, Teresa Sanchez, et al. “Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells.J Biol Chem 283, no. 44 (October 31, 2008): 30363–75. https://doi.org/10.1074/jbc.M804392200.
Estrada R, Zeng Q, Lu H, Sarojini H, Lee J-F, Mathis SP, et al. Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells. J Biol Chem. 2008 Oct 31;283(44):30363–75.
Estrada, Rosendo, et al. “Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells.J Biol Chem, vol. 283, no. 44, Oct. 2008, pp. 30363–75. Pubmed, doi:10.1074/jbc.M804392200.
Estrada R, Zeng Q, Lu H, Sarojini H, Lee J-F, Mathis SP, Sanchez T, Wang E, Kontos CD, Lin C-Y, Hla T, Haribabu B, Lee M-J. Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells. J Biol Chem. 2008 Oct 31;283(44):30363–30375.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

October 31, 2008

Volume

283

Issue

44

Start / End Page

30363 / 30375

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Receptors, Lysosphingolipid
  • PTEN Phosphohydrolase
  • Models, Biological
  • Humans
  • Genes, Dominant
  • Endothelial Cells
  • Chemotaxis
  • Cellular Senescence