Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling

Background: Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1 alpha and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH. Methods: The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1 alpha/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1 alpha or PDGF-BB. Results: HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1 alpha and PDGF-BB in HIV-Tg rats. The upregulation of both HIF-1 alpha and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120(CM). Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1 alpha small interfering RNA resulted in abrogation of gp-120(CM) mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1 alpha plays critical role in gp120 mediated upregulation of PDGF-BB. Conclusion: In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1 alpha dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.