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Rapamycin inhibits transforming growth factor β-induced peritoneal angiogenesis by blocking the secondary hypoxic response.

Sekiguchi Y, Zhang J, Patterson S, Liu L, Hamada C, Tomino Y, Margetts PJ - J. Cell. Mol. Med. (2012)

Bottom Line: In primary mesothelial cell culture, rapamycin had no effect on TGFβ-induced vascular endothelial growth factor (VEGF) but did suppress hypoxia-induced VEGF.The fibrogenic effects of HIF1α were Smad3 dependent.The hypoxic response is mediated partly through HIF1α and the mTOR inhibitor rapamycin blocks the hypoxic-induced angiogenic effects but does not affect the direct TGFβ-mediated fibrosis and angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

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Related in: MedlinePlus

Primary rat mesothelial cells were cultured and exposed to varying concentrations of rapamycin and then grown for 12 or 24 hrs in normal or hypoxic (1% O2) conditions. (A) Hypoxia significantly up-regulated HIF1α protein expression (P = 0.006, normoxia versus 12 hrs hypoxia; P = 0.001, normoxia versus 24 hrs hypoxia, two-way ANOVA) and this was blocked by rapamycin. (B) Representative blot. (C) Cell culture supernatant was assayed for VEGF by ELISA. Hypoxia significantly increased VEGF expression after 24 hrs (P < 0.001 for 24 hrs hypoxia compared with 12 hrs, or normoxia by two-way ANOVA) and this effect was blocked by rapamycin (n = 3 samples for each group).
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fig05: Primary rat mesothelial cells were cultured and exposed to varying concentrations of rapamycin and then grown for 12 or 24 hrs in normal or hypoxic (1% O2) conditions. (A) Hypoxia significantly up-regulated HIF1α protein expression (P = 0.006, normoxia versus 12 hrs hypoxia; P = 0.001, normoxia versus 24 hrs hypoxia, two-way ANOVA) and this was blocked by rapamycin. (B) Representative blot. (C) Cell culture supernatant was assayed for VEGF by ELISA. Hypoxia significantly increased VEGF expression after 24 hrs (P < 0.001 for 24 hrs hypoxia compared with 12 hrs, or normoxia by two-way ANOVA) and this effect was blocked by rapamycin (n = 3 samples for each group).

Mentions: As previously demonstrated [26], rapamycin significantly reduced HIF1α and VEGF expression in mesothelial cells exposed to 1% oxygen for 12 or 24 hrs (Fig. 5). Hypoxia significantly up-regulated HIF1α protein expression. Rapamycin significantly decreased HIF1α protein expression at both 12 and 24 hrs (Fig. 5A and B). By two-way ANOVA, hypoxia significantly increased VEGF expression after 24 hrs of hypoxia. Rapamycin significantly decreased hypoxia-induced VEGF expression in a dose-dependent manner (Fig. 5C).


Rapamycin inhibits transforming growth factor β-induced peritoneal angiogenesis by blocking the secondary hypoxic response.

Sekiguchi Y, Zhang J, Patterson S, Liu L, Hamada C, Tomino Y, Margetts PJ - J. Cell. Mol. Med. (2012)

Primary rat mesothelial cells were cultured and exposed to varying concentrations of rapamycin and then grown for 12 or 24 hrs in normal or hypoxic (1% O2) conditions. (A) Hypoxia significantly up-regulated HIF1α protein expression (P = 0.006, normoxia versus 12 hrs hypoxia; P = 0.001, normoxia versus 24 hrs hypoxia, two-way ANOVA) and this was blocked by rapamycin. (B) Representative blot. (C) Cell culture supernatant was assayed for VEGF by ELISA. Hypoxia significantly increased VEGF expression after 24 hrs (P < 0.001 for 24 hrs hypoxia compared with 12 hrs, or normoxia by two-way ANOVA) and this effect was blocked by rapamycin (n = 3 samples for each group).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3822704&req=5

fig05: Primary rat mesothelial cells were cultured and exposed to varying concentrations of rapamycin and then grown for 12 or 24 hrs in normal or hypoxic (1% O2) conditions. (A) Hypoxia significantly up-regulated HIF1α protein expression (P = 0.006, normoxia versus 12 hrs hypoxia; P = 0.001, normoxia versus 24 hrs hypoxia, two-way ANOVA) and this was blocked by rapamycin. (B) Representative blot. (C) Cell culture supernatant was assayed for VEGF by ELISA. Hypoxia significantly increased VEGF expression after 24 hrs (P < 0.001 for 24 hrs hypoxia compared with 12 hrs, or normoxia by two-way ANOVA) and this effect was blocked by rapamycin (n = 3 samples for each group).
Mentions: As previously demonstrated [26], rapamycin significantly reduced HIF1α and VEGF expression in mesothelial cells exposed to 1% oxygen for 12 or 24 hrs (Fig. 5). Hypoxia significantly up-regulated HIF1α protein expression. Rapamycin significantly decreased HIF1α protein expression at both 12 and 24 hrs (Fig. 5A and B). By two-way ANOVA, hypoxia significantly increased VEGF expression after 24 hrs of hypoxia. Rapamycin significantly decreased hypoxia-induced VEGF expression in a dose-dependent manner (Fig. 5C).

Bottom Line: In primary mesothelial cell culture, rapamycin had no effect on TGFβ-induced vascular endothelial growth factor (VEGF) but did suppress hypoxia-induced VEGF.The fibrogenic effects of HIF1α were Smad3 dependent.The hypoxic response is mediated partly through HIF1α and the mTOR inhibitor rapamycin blocks the hypoxic-induced angiogenic effects but does not affect the direct TGFβ-mediated fibrosis and angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Show MeSH
Related in: MedlinePlus