title: Cigarette smoke-induced pulmonary endothelial dysfunction is partially suppressed by sildenafil.
abstract: Cigarette smoke mediated oxidative stress and endothelial dysfunction are important processes in the pathogenesis of several lung disorders. In this study we evaluated the effect of PDE5 inhibition on pulmonary artery endothelial dysfunction induced by cigarette smoke in vitro. Human pulmonary artery endothelial cells (HPAEC) were incubated in the absence or presence of PDE5 inhibitor sildenafil (10 nM-1 microM), PKG agonist 8-Br-cGMP (1mM), or the antioxidants dyphenyleneiodonium (DPI 1 microM) and N-acetylcysteine (NAC 1mM) for 30 min. Then, cigarette smoke extract (CSE) was added for 24h. CSE (2.5-10%)-induced ROS generation was suppressed by DPI, and partially reversed by sildenafil and 8-Br-cGMP. Decreases in intracellular levels of cGMP and extracellular NO induced by CSE were reversed by sildenafil and DPI. Furthermore, CSE-induced pg91(phox) and PDE5 mRNA overexpression were suppressed by both sildenafil and DPI. CSE (2.5-10%) induced upregulation of IL-6, IL-8 and Ang-2, and decreased Ang-1 expression in parallel to apoptosis which were partially suppressed by sildenafil, 8-Br-cGMP, DPI and NAC. This study demonstrates that PDE5 inhibition attenuates the oxidant burden and the inflammatory and remodeling effects of CSE in human HPAEC which may contribute to the therapeutic value of PDE5 inhibitors for pulmonary disorders coursing with endothelial dysfunction.
authors.affiliation: Research Unit, University General Hospital Consortium, Valencia, Spain. xmilara@hotmail.com
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.forename: Gustavo
authors.initials: G
authors.lastname: Juan
authors.forename: Jose L
authors.initials: JL
authors.lastname: Ortiz
authors.forename: Ricardo
authors.initials: R
authors.lastname: Guijarro
authors.forename: Mercedes
authors.initials: M
authors.lastname: Losada
authors.forename: Adela
authors.initials: A
authors.lastname: Serrano
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Morcillo
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis; D010879:Piperazines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D012906:Smoke / Q000009:adverse effects*; D013450:Sulfones / Q000494:pharmacology*; D014026:Nicotiana; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D010879:Piperazines; D011687:Purines; D012906:Smoke; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate