Human immunodeficiency virus-1 transgene expression increases pulmonary vascular resistance and exacerbates hypoxia-induced pulmonary hypertension development

• Type of Material: Article
• Authors: Kristi M. Porter, Emory University; Erik R. Walp, Emory University; Shawn C. Elms, Emory University; Robert Raynor, Emory University; Patrick O. Mitchell, Emory University; David M Guidot, Emory University; Roy Sutliff, Emory University
• Language: English
• Date: 2013-01
• Publisher: Medknow Publications
• Publication Version: Final Published Version
• Copyright Statement: © Pulmonary Circulation
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://www.pulmonarycirculation.org/article.asp?issn=2045-8932;year=2013;volume=3;issue=1;spage=58;epage=67;aulast=Porter;type=0
• Title of Journal or Parent Work: Pulmonary Circulation
• ISSN: 2045-8932
• Volume: 3
• Issue: 1
• Start Page: 58
• End Page: 67
• Grant/Funding Information: This research was supported by HL070892 to RLS, the National Science Foundation Award #0450303, Subaward # I.66-606-63 to Emory University, the Pharmacological Sciences Training Grant TM GM 008602 and the National Institute of Allergy and Infectious Diseases 1.F31.AI084460
• Keywords: chronic hypoxia; pulmonary hypertension; human immunodeficiency virus
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial resistance and vessel remodeling. Patients living with human immunodeficiency virus-1 (HIV-1) have an increased susceptibility to develop severe pulmonary hypertension (PH) irrespective of their CD4+ lymphocyte counts. While the underlying cause of HIV-PAH remains unknown, the interaction of HIV-1 proteins with the vascular endothelium may play a critical role in HIV-PAH development. Hypoxia promotes PH in experimental models and in humans, but the impact of HIV-1 proteins on hypoxia-induced pulmonary vascular dysfunction and PAH has not been examined. Therefore, we hypothesize that the presence of HIV-1 proteins and hypoxia synergistically augment the development of pulmonary vascular dysfunction and PH. We examined the effect of HIV-1 proteins on pulmonary vascular resistance by measuring pressure-volume relationships in isolated lungs from wild-type (WT) and HIV-1 Transgenic (Tg) rats. WT and HIV-1 Tg rats were exposed to 10% O2 for four weeks to induce experimental pulmonary hypertension to assess whether HIV-1 protein expression would impact the development of hypoxia-induced PH. Our results demonstrate that HIV-1 protein expression significantly increased pulmonary vascular resistance (PVR). HIV-1 Tg mice demonstrated exaggerated pulmonary vascular responses to hypoxia as evidenced by greater increases in right ventricular systolic pressures, right ventricular hypertrophy and vessel muscularization when compared to wild-type controls. This enhanced PH was associated with enhanced expression of HIF-1α and PCNA. In addition, in vitro studies reveal that medium from HIV-infected monocyte derived macrophages (MDM) potentiates hypoxia-induced pulmonary artery endothelial proliferation. These results indicate that the presence of HIV-1 proteins likely impact pulmonary vascular resistance and exacerbate hypoxia-induced PH.