title: Hypoxia-driven proliferation of human pulmonary artery fibroblasts: cross-talk between HIF-1alpha and an autocrine angiotensin system.
abstract: Pulmonary artery adventitial fibroblasts (FBPA) may play a central role in lung vascular remodeling under conditions of hypoxia and inflammation, the result being pulmonary hypertension and cor pulmonale. In cultured human FBPA, both angiotensin II (Ang II) and hypoxia promoted cell cycle progression and cell proliferation and suppressed apoptosis. These effects were further enhanced when both stimuli were applied simultaneously. Hypoxia elevated the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) and increased the expression of genes regulated by the hypoxia-responsive element (HRE). Up-regulation of both angiotensin-converting enzyme (ACE) and Ang II receptor type 1 (AT1) was also observed. Exogenous Ang II further increased HIF/HRE-dependent signaling in FBPA, whereas suppression of the autocrine ACE-Ang II-AT1 loop with inhibitors of ACE, AT1, and phosphatidylinositol 3-kinase (PI3K) reduced the proliferative response to both hypoxia and exogenous Ang II. Overexpression of HIF-1alpha by transient transfection caused the same proliferative effect and up-regulation of AT1 expression that were observed under hypoxic conditions. In contrast, small interfering RNA targeting HIF-1alpha inhibited hypoxia-induced ACE and AT1 expression. Our studies indicate that the ACE-Ang II-AT1 system serves as a positive feedback loop and fosters FBPA proliferation under hypoxic conditions, with the PI3K-HIF-HRE axis as the central effector pathway. This pathway may thus facilitate vascular remodeling under hypoxic conditions.
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine, Justus-Liebig-University Giessen, Giessen, Germany. stefanie krick@innere.med.uni-giessen.de
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krick
authors.forename: Jörg
authors.initials: J
authors.lastname: Hänze
authors.forename: Bastian
authors.initials: B
authors.lastname: Eul
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seay
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lohmeyer
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Frank
authors.initials: F
authors.lastname: Rose
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000809:Angiotensins / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003238:Connective Tissue / Q000473:pathology; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011651:Pulmonary Artery / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A