Hypoxia-driven proliferation of human pulmonary artery fibroblasts: cross-talk between HIF-1α and an autocrine angiotensin system

摘要: 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 cor pulmonale. In cultured human FBPA, both angiotensin II (Ang II) promoted cell cycle progression proliferation suppressed apoptosis. These effects were further enhanced when stimuli applied simultaneously. Hypoxia elevated expression hypoxia-inducible factor 1alpha (HIF-1alpha) increased genes regulated by hypoxia-responsive element (HRE). Up-regulation angiotensin-converting enzyme (ACE) Ang receptor type 1 (AT1) was also observed. Exogenous HIF/HRE-dependent signaling whereas suppression autocrine ACE-Ang II-AT1 loop with inhibitors ACE, AT1, phosphatidylinositol 3-kinase (PI3K) reduced proliferative response to exogenous II. Overexpression HIF-1alpha transient transfection caused same effect up-regulation AT1 that observed hypoxic conditions. contrast, small interfering RNA targeting inhibited hypoxia-induced ACE expression. Our studies indicate system serves as positive feedback fosters FBPA conditions, PI3K-HIF-HRE axis effector pathway. This pathway thus facilitate