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In bovine pulmonary artery endothelial cells, SIN-1 and<jats:italic>S<\/jats:italic>-nitroso-<jats:italic>N<\/jats:italic>-acetyl-<jats:sc>d,l<\/jats:sc>-penicillamine (SNAP) at 1 to 100 \u03bcmol\/L induced the synthesis of HO-1 protein in a concentration-dependent fashion up to 3-fold over basal levels. HO-1 induction by SIN-1 was inhibited in the presence of the NO scavenger phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide and the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-<jats:italic>a<\/jats:italic>]quinoxalin-1-one. 8-Bromo-cGMP (1 to 100 \u03bcmol\/L) and dibutyryl cGMP (1 to 100 \u03bcmol\/L) as well as the activator of particulate guanylyl cyclase atrial natriuretic peptide (1 to 100 nmol\/L) produced increases in HO-1 protein similar to those produced by SIN-1. SIN-1 and 8-bromo-cGMP increased heme oxygenase activity (bilirubin formation). Cytoprotection by NO donors was abrogated in the presence of the heme oxygenase inhibitor tin protoporphyrin IX. Pretreatment of cells with a phosphorothioate-linked HO-1 antisense oligonucleotide prevented protection by SIN-1 or 8-bromo-cGMP against tumor necrosis factor-\u03b1 cytotoxicity, whereas sense and scrambled HO-1 were without effect under these conditions. Our results show for the first time that HO-1 is a cGMP-sensitive endothelial gene and establish conclusively a causal relationship between HO-1 induction and endothelial protection by the NO\/cGMP system. By targeting cytoprotective HO-1, NO donors may therefore be expected to induce antioxidant, antiatherogenic, and anti-inflammatory effects.<\/jats:p>","DOI":"10.1161\/01.atv.20.5.1209","type":"journal-article","created":{"date-parts":[[2011,6,17]],"date-time":"2011-06-17T19:44:19Z","timestamp":1308339859000},"page":"1209-1215","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":109,"title":["Heme Oxygenase-1 Is a cGMP-Inducible Endothelial Protein and Mediates the Cytoprotective Action of Nitric Oxide"],"prefix":"10.1161","volume":"20","author":[{"given":"Tobias","family":"Polte","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle, Germany, and the Department of Pediatrics (P.A.D.), Stanford University School of Medicine, Stanford, 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