Conference: 2008 International PHA Conference and Scientific Sessions
Release Date: 06.20.2008
Presentation Type: Abstracts
Bull T.M.1, Meadows C.A.1, Campbell T.B.2, Geraci M.A.1
1. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Pulmonary Hypertension Center and
2. Division of Infectious Disease, University of Colorado Health Sciences Center, Denver, CO, USA
BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is associated with endothelial cell proliferation and resistance to apoptosis within the pulmonary vasculature. While the etiology for these cellular abnormalities is unclear both viral infection and mutations in the receptor for bone morphogenic protein receptor-2 (BMPR2) have been implicated. We have demonstrated evidence of Human Herpesvirus-8 (HHV-8) infection within the plexiform lesions of patients with IPAH. We are now investigating mechanisms by which HHV-8 infection of pulmonary endothelial cells could cause pulmonary hypertension.
METHODS: Human pulmonary microvascular endothelial cells (HMVEC-L) were cultured and exposed to harvested HHV-8. After confirming infection, the cells were assayed for informative changes in gene and protein expression and changes in cellular apoptosis.
RESULTS: HHV-8 infection of HMVEC-L results in marked alteration of gene and protein expression affecting a number of angiogenic and apoptotic pathways. HHV-8 infection of HMVEC-L significantly increases expression of interleukin 6 (Il-6) and thre matrix metalloproteinases (MMPs)-1, 2 and 10 while significantly decreasing the expression of bone morphogenic protein receptor-1a (BMPR1a) and bone morphogenic protein 4 (BMP4). HMVEC-L infected with HHV-8 become resistant to apoptosis.
CONCLUSION: Infection of human pulmonary microvascular endothelial cells with HHV-8 results in significant cellular alterations. These changes include down regulation of a receptor and ligand integral to the BMP signaling cascade, a pathway of recognized importance in the development of PAH. HHV8 infection also increases proteins previously implicated in the development of PAH such as IL-6 and the MMPs. Lastly, HMVEC-L infected with HHV-8 develop apoptosis resistance, a phenotypic change relevant to the development of the plexiform lesion and pulmonary hypertension.