Heme oxygenase attenuates angiotensin II-mediated increase in cyclooxygenase-2 activity in human femoral endothelial cells.
Heme oxygenase (HO) regulates cellular heme levels and catalyzes the formation of bilirubin and carbon monoxide. We hypothesize that the status of the endothelial HO system influences the angiotensin (Ang) II-induced increase in the endothelial production of prostaglandin I2 (PGI2) (measured as 6-keto-PGF1alpha) and prostaglandin E2 (PGE2), eicosanoids that modulate the vascular actions of Ang II. In the present study, we determined the effect of interventions that suppress HO activity or induce HO-1 gene expression on Ang II-mediated increase in 6-keto-PGF1alpha and PGE2 in cultures of human femoral artery endothelial cells. Incubation of endothelial cells with Ang II (100 ng/mL) for 24 hours increased the levels of both 6-keto-PGF1alpha and PGE2 in the culture media. This effect of Ang II on prostaglandin production by endothelial cells was attenuated in cells treated with SnCl2 (10 micromol/L), an inducer of HO-1, but was magnified in cells treated with the HO inhibitor ZnDPP or heme. Upregulation of HO-1 gene expression by retrovirus-mediated delivery of the human HO-1 gene also attenuated heme and Ang II-induced prostaglandin synthesis. Of note, prostaglandin synthesis by lysates of endothelial cells stimulated with heme or Ang II appear to involve COX-2, because it was blunted by NS-398, which is presumed to inhibit COX-2 specifically. These results indicate that overexpression of the HO system exerts an inhibitory influence on Ang II-induced synthesis of prostaglandins by endothelial cells.
Li Volti
Giovanni
G
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Seta
Francesca
F
Schwartzman
Michal L
ML
Nasjletti
Alberto
A
Abraham
Nader G
NG
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation; D005263:Femoral Artery / Q000166:cytology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D014161:Transduction, Genetic
D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D000804:Angiotensin II; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases