Hypoxia up-regulates PGI-synthase and increases PGI2 release in human vascular cells exposed to inflammatory stimuli.
2011, J Lipid Res. 2011 Feb 4. [Epub ahead of print]
Camacho M, Rodriguez C, Guadall A, Alcolea S, Orriols M, Escudero JR, Martinez-Gonzalez J, Vila L.
Autores del centro relacionados: Martínez-González Jose, Rodríguez Cristina, Guadall Anna.
Camacho M, Rodriguez C, Guadall A, Alcolea S, Orriols M, Escudero JR, Martinez-Gonzalez J, Vila L.
Autores del centro relacionados: Martínez-González Jose, Rodríguez Cristina, Guadall Anna.
Institute of Biomedical Research (II-B Sant Pau), Spain;
Abstract
Hypoxia affects vascular function, cell metabolism, survival, growth and motility, processes partially regulated by prostanoids. We analyzed the effect of hypoxia and inflammation on key enzymes involved in prostanoid biosynthesis in human vascular cells. In human vascular smooth muscle cells (VSMC) hypoxia and interleukin-1β synergistically increased PGI(2) but not PGE(2) release, thereby increasing the PGI(2)/PGE(2) ratio. Concomitantly, these stimuli up-regulated cyclooxygenase-2 (COX-2) expression (mRNA and protein) and COX activity. Interestingly, hypoxia enhanced PGI-synthase (PGIS) expression and activity in VSMC and human endothelial cells. Hypoxia did not significantly modify the inducible microsomal-PGE-synthase (mPGES-1). HIF-1α silencing abrogated hypoxia-induced PGIS up-regulation. PGIS transcriptional activity was enhanced by hypoxia; however, the minimal PGIS promoter responsive to hypoxia (-131 bp) did not contain any putative hypoxia response element (HRE), suggesting that HIF-1 does not directly drive PGIS transcription. Serial deletion and site-directed mutagenesis studies suggest several transcription factors participate cooperatively. Plasma levels of the stable metabolite of PGI(2) and PGIS expression in several tissues were also up-regulated in mice exposed to hypoxia. These data suggest that PGIS up-regulation is part of the adaptive response of vascular cells to hypoxic stress and could play a role in counteracting the deleterious effect of inflammatory stimuli.
Abstract
Hypoxia affects vascular function, cell metabolism, survival, growth and motility, processes partially regulated by prostanoids. We analyzed the effect of hypoxia and inflammation on key enzymes involved in prostanoid biosynthesis in human vascular cells. In human vascular smooth muscle cells (VSMC) hypoxia and interleukin-1β synergistically increased PGI(2) but not PGE(2) release, thereby increasing the PGI(2)/PGE(2) ratio. Concomitantly, these stimuli up-regulated cyclooxygenase-2 (COX-2) expression (mRNA and protein) and COX activity. Interestingly, hypoxia enhanced PGI-synthase (PGIS) expression and activity in VSMC and human endothelial cells. Hypoxia did not significantly modify the inducible microsomal-PGE-synthase (mPGES-1). HIF-1α silencing abrogated hypoxia-induced PGIS up-regulation. PGIS transcriptional activity was enhanced by hypoxia; however, the minimal PGIS promoter responsive to hypoxia (-131 bp) did not contain any putative hypoxia response element (HRE), suggesting that HIF-1 does not directly drive PGIS transcription. Serial deletion and site-directed mutagenesis studies suggest several transcription factors participate cooperatively. Plasma levels of the stable metabolite of PGI(2) and PGIS expression in several tissues were also up-regulated in mice exposed to hypoxia. These data suggest that PGIS up-regulation is part of the adaptive response of vascular cells to hypoxic stress and could play a role in counteracting the deleterious effect of inflammatory stimuli.
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