The Role of Arachidonate 5-Lipoxygenase in HIV-associated Pulmonary Hypertension 公开
Porter, Kristi Michelle (2012)
Abstract
The Role of Arachidonate 5-Lipoxygenase in
HIV-associated Pulmonary Hypertension
By Kristi Michelle Porter
There are approximately 39 million people infected with
human immunodeficiency virus type-1 (HIV-1) worldwide.
Previously, the hallmark characteristic of HIV-1 was enhanced
susceptibility to opportunistic infections, such as Pneumocystis
pneumonia and Haemophilus influenzae. The
advent of highly active antiretroviral therapy (HAART) has greatly
reduced the incidence of infectious disorders and improved
survival. However, HIV-infected persons
now demonstrate a heightened risk of developing
non-infectious lung disorders such as HIV-associated
pulmonary arterial hypertension (HIV-PAH). HIV-PAH is a disorder
characterized by increased pulmonary vascular tone and remodeling.
PAH in HIV-1 patients occurs more frequently and progresses more
rapidly than in uninfected individuals irrespective of
CD4+ lymphocyte counts. These findings suggest that
the interaction of HIV-1 proteins with the pulmonary vascular
endothelium may play a critical role in HIV-PAH development by
altering pathways that regulate vascular tone and
remodeling such as arachidonate 5-lipoxygenase
(ALOX5). We hypothesize that the presence of HIV-1
proteins and hypoxia exposure augment pulmonary vascular
dysfunction and PAH by altering ALOX5 expression and
activity.
The central hypothesis of this work is hypoxia exposure and HIV-1 proteins concomitantly promote the development of HIV-PAH by stimulating endothelial cell proliferation and vascular remodeling via increased 5-lipoxygenase expression and activity. In vitro results demonstrate that exposure of pulmonary artery endothelial cells to prolonged hypoxia, medium from HIV-infected macrophages and HIV-1 Tat increases ALOX5 expression. Research also reveals that hypoxia exposure induces endothelial proliferation in an ALOX5-dependent manner, and that medium from HIV-infected macrophages potentiates hypoxia-induced cellular proliferation. Furthermore, our findings indicate that excessive reactive oxygen species production and reduced antioxidant expression mediate the hypoxia-induced increases in ALOX5 and cell proliferation. Additionally, in vivo results reveal that HIV-1 transgenic animals develop an exacerbated form of hypoxia-induced PH when compared to wild-type animals. The ALOX5 pathway is implicated in the increased severity of PH in HIV-1 transgenic animals, as they demonstrate elevated levels of ALOX5 and its metabolites. Collectively, these results indicate that the presence of HIV-1 proteins likely impact pulmonary vascular resistance and increase susceptibility to hypoxia-induced PH by stimulating the ALOX5 pathway.
Table of Contents
Chapter 1. Introduction - Page 1
Chapter 2. Methods and Materials - Page 52
Introduction - Page 63
Results - Page 66
Introduction - Page 89
Results - Page 91
Discussion - Page 110
Introduction - Page 116
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