Heme oxygenase attenuated angiotensin II-mediated increase in cyclooxygenase activity and decreased isoprostane F2alpha in endothelial cells.
Heme oxygenase (HO) regulates cellular heme levels and catalyzes the formation of bilirubin and carbon monoxide (CO). We hypothesized that the status of the endothelial HO system influences the angiotensin (Ang) II-induced increase in the endothelial cell (EC) production of PGE2, eicosanoids which modulate the vascular actions of Ang II. In this study, we investigated the effect of interventions that suppress HO activity or induce HO-1 gene expression on Ang II-mediated increase in PGE2 in cultures of human microvessel endothelial cells (EC). Incubation of EC with Ang II (100 ng/ml) for 24 h increased the levels of PGE2 in the culture media. This effect of Ang II on prostaglandin production by EC was attenuated in cells treated with heme, but was magnified in cells treated with the HO inhibitor, Stannis mesoporphyrin (SnMP). Upregulation of HO-1 gene expression by retrovirus-mediated delivery of the human HO-1 gene attenuated heme and Ang II-induced prostaglandin synthesis. We also investigated the physiological significance of human HO-1 overexpression on attenuation of Ang II-mediated oxidative stress. Decreases in COMET levels were found in EC transduced with the HO-1 gene. These results indicate that overexpression of the HO system in EC exerts an inhibitory influence on Ang II-induced synthesis of prostaglandins and attenuates DNA damage caused by exposure to Ang II.
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. nader_abraham@nymc.edu
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D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D028421:Isoprostanes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D028421:Isoprostanes; D008565:Membrane Proteins; C438786:isoprostane F2alpha III; D000804:Angiotensin II; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D011451:Prostaglandin-Endoperoxide Synthases