Effect of Prostaglandin-J 2 on VEGF Synthesis Depends on the Induction of Heme Oxygenase-1

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-Δ^12,14prostaglandin-J₂(15d-PGJ₂), a natural ligand of peroxisome proliferator-activated receptor-γ transcription factor. In macrophages and vascular smooth muscle cells, 15d-PGJ₂ 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-PGJ₂-mediated regulation of VEGF production by human microvascular endothelial cells (HMEC-1). Resting HMEC-1 released ∼20 pg/ml VEGF protein after 24 h of incubation. Treatment of cells with 15d-PGJ₂ (1-10 μM) significantly and dose-dependently increased the VEGF promoter activity, mRNA expression, and protein secretion. In the same cells, 15d-PGJ₂ 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-PGJ₂ 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-PGJ₂ on VEGF synthesis. Thus, we postulate that the up-regulation of VEGF expression in response to 15d-PGJ₂ in HMEC-1 is mediated by the activation of HO-1.