Hypoxia-induced pulmonary hypertension (HPH) is a condition that increases mortality in patients with cardiopulmonary diseases (e.g., chronic obstructive pulmonary disease, COPD) and obstructive sleep apnea. Multifactorial etiology involving abnormalities in pulmonary artery smooth muscle (PASMC) and endothelial (PAEC) cells has been implicated in HPH. Our data demonstrate that a) hypoxia upregulates NotchS in lung tissues and PASMC;b) hypoxia-induced pulmonary vascular remodeling is inhibited in Notch3 knockout mice;and c) Jaggedl, NotchS and Hes5 are all upregulated in lung tissues and PASMC from patients with PH compared with normal subjects and normotensive patients. Furthermore, our observations indicate that: /) hypoxia upregulates TRP channels and increases AP-1 binding activity in PAEC;/?/) hypoxia inhibits Kv channels in PASMC;and ///) Kv channel activity is decreased whereas TRP channel activity is increased in PASMC from PH patients compared with PASMC from normotensive subjects. These data imply that Notch signaling may interact with ion channels (e.g., Kv and TRP channels) and other signal transduction cascades in regulating pulmonary vascular remodeling, a major cause for the elevated pulmonary vascular resistance in animals and patients with HPH. The goal of this study is to determine whether and how Notch signaling, by interacting with hypoxia-sensitive membrane channels, is involved in a) the initiation and progression of HPH and b) the variability of pulmonary vascular susceptibility to hypoxia. The central hypotheses are that /) selective Notch signaling genes and ion channels in PASMC/PAEC are involved in hypoxia-mediated changes in pulmonary vascular function/structure and //) differential regulation of these genes (i.e., expression and function) by hypoxia in PASMC/PAEC determines hypoxia susceptibility.
Three Specific Aims are proposed in this project: 1) To characterize the effects of acute, intermittent and sustained hypoxia on the expression and function of genes in the Notch signaling pathway and genes encoding Kv and TRP channels in normal PASMC and PAEC from humans and mice;2) To determine and compare the expression and function of genes in the Notch signaling pathway and genes encoding Kv and TRP channels in PASMC and PAEC isolated from normoxic control mice and HPH mice;and 3) To determine and compare expression and function of genes in the Notch signaling pathway and Kv and TRP channels in PASMC and PAEC isolated from /) normotensive patients, ii) COPD patients with HPH, iii) COPD patients without HPH, and iv) patients with pulmonary arterial hypertension.

Public Health Relevance

Project 2 will investigate potential mechanisms that cause pulmonary hypertension (high blood pressure in the lung) during hypoxia. We will focus on studying abnormalities in lung tissues and vascular cells isolated from animals and patients with pulmonary hypertension. Completion of this study will provide important information for the development of novel therapeutic approaches for patients with cardiopulmonary disease.

National Institute of Health (NIH)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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University of California San Diego
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