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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL098053-04
Application #
8511796
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$368,158
Indirect Cost
$132,840
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Yamamura, Hisao; Yamamura, Aya; Ko, Eun A et al. (2014) Activation of Notch signaling by short-term treatment with Jagged-1 enhances store-operated Ca(2+) entry in human pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 306:C871-8
Smith, Kimberly A; Yuan, Jason X-J (2014) Hypoxia-inducible factor-1? in pulmonary arterial smooth muscle cells and hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med 189:245-6
Lim, Hui-Ying; Wang, Weidong; Chen, Jianming et al. (2014) ROS regulate cardiac function via a distinct paracrine mechanism. Cell Rep 7:35-44
Nishimura, Mayuko; Kumsta, Caroline; Kaushik, Gaurav et al. (2014) A dual role for integrin-linked kinase and ?1-integrin in modulating cardiac aging. Aging Cell 13:431-40
Kang, Yunyi; Tiziani, Stefano; Park, Goonho et al. (2014) Cellular protection using Flt3 and PI3K? inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity. Nat Commun 5:3672
Song, Shanshan; Yamamura, Aya; Yamamura, Hisao et al. (2014) Flow shear stress enhances intracellular Ca2+ signaling in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension. Am J Physiol Cell Physiol 307:C373-83
Lathen, Christopher; Zhang, Yu; Chow, Jennifer et al. (2014) ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. Circulation 130:1179-91
Pfeiffer, E R; Wright, A T; Edwards, A G et al. (2014) Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing. J Mol Cell Cardiol 76:265-74
Ronen, Roy; Zhou, Dan; Bafna, Vineet et al. (2014) The genetic basis of chronic mountain sickness. Physiology (Bethesda) 29:403-12
Gan, Zhuohui; Wang, Jianwu; Salomonis, Nathan et al. (2014) MAAMD: a workflow to standardize meta-analyses and comparison of affymetrix microarray data. BMC Bioinformatics 15:69

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