Effect of prostaglandin-J(2) on VEGF synthesis depends on the induction of heme oxygenase-1

Antioxid Redox Signal. 2002 Aug;4(4):577-85. doi: 10.1089/15230860260220076.

Abstract

Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades heme to carbon monoxide, iron ions, and biliverdin. Its expression can be induced by 15-deoxy-Delta(12,14)prostaglandin-J(2) (15d-PGJ(2)), a natural ligand of peroxisome proliferator-activated receptor-gamma transcription factor. In macrophages and vascular smooth muscle cells, 15d-PGJ(2) up-regulates the expression of vascular endothelial growth factor (VEGF), a fundamental regulator of angiogenesis. Here we investigated the involvement of HO-1 in the 15d-PGJ(2)-mediated regulation of VEGF production by human microvascular endothelial cells (HMEC-1). Resting HMEC-1 released approximately 20 pg/ml VEGF protein after 24 h of incubation. Treatment of cells with 15d-PGJ(2) (1-10 microM) significantly and dose-dependently increased the VEGF promoter activity, mRNA expression, and protein secretion. In the same cells, 15d-PGJ(2) potently induced the expression of HO-1 protein that correlated with HO-1 promoter activity. Activation of HO-1 with hemin or ectopic overexpression of HO-1 in HMEC-1 perfectly mimicked the effect of 15d-PGJ(2) and led to increased VEGF production. Importantly, the inhibition of the HO-1 pathway by tin protoporphyrin-IX significantly reduced the stimulatory effect of 15d-PGJ(2) on VEGF synthesis. Thus, we postulate that the up-regulation of VEGF expression in response to 15d-PGJ(2 )in HMEC-1 is mediated by the activation of HO-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / genetics
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Enzyme Activation
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • Genes, Reporter
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Heme Oxygenase-1
  • Hemin / pharmacology
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Interleukin-8 / metabolism
  • Lymphokines / biosynthesis*
  • Lymphokines / genetics
  • Membrane Proteins
  • Mice
  • Photosensitizing Agents / chemistry
  • Photosensitizing Agents / metabolism
  • Promoter Regions, Genetic
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology*
  • Protoporphyrins / chemistry
  • Protoporphyrins / metabolism
  • RNA, Messenger / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-8
  • Lymphokines
  • Membrane Proteins
  • Photosensitizing Agents
  • Protoporphyrins
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • 9-deoxy-delta-9-prostaglandin D2
  • Hemin
  • protoporphyrin IX
  • HMOX1 protein, human
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Prostaglandin D2