Genetic and Molecular Mechanisms in Hypoxia-Induced Pulmonary Hypertension

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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 fissues 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 fissues and PASMC from pafients 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 acfivity 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 transducfion cascades in regulafing pulmonary vascular remodeling, a major cause for the elevated pulmonary vascular resistance in animals and pafients 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 inifiafion and progression of HPH and b) the variability of pulmonary vascular suscepfibility 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 funcfion/structure and //) differenfial regulafion 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 funcfion of genes in the Notch signaling pathway and Kv and TRP channels in PASMC and PAEC isolated from /) normotensive pafients, ii) COPD patients with HPH, iii) COPD pafients without HPH, and iv) pafients with pulmonary arterial hypertension.