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.

Public Health Relevance

Project 2 will investigate potenfial mechanisms that cause pulmonary hypertension (high blood pressure in the lung) during hypoxia. We will focus on studying abnormalities in lung fissues 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)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Walls, Stanley M; Cammarato, Anthony; Chatfield, Dale A et al. (2018) Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy. Cell Rep 22:2702-2715
Zanon, Alessandra; Kalvakuri, Sreehari; Rakovic, Aleksandar et al. (2017) SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila. Hum Mol Genet 26:2412-2425
Diop, Soda Balla; Birse, Ryan T; Bodmer, Rolf (2017) High Fat Diet Feeding and High Throughput Triacylglyceride Assay in Drosophila Melanogaster. J Vis Exp :
Zarndt, Rachel; Walls, Stanley M; Ocorr, Karen et al. (2017) Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila. Circ Cardiovasc Genet 10:
Pamenter, Mathhew E; Powell, Frank L (2016) Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis. Compr Physiol 6:1345-85
Gan, Zhuohui; Fu, Zhenxing; Stowe, Jennifer C et al. (2016) A Protocol to Collect Specific Mouse Skeletal Muscles for Metabolomics Studies. Methods Mol Biol 1375:169-79
Díaz-Trelles, Ramón; Scimia, Maria Cecilia; Bushway, Paul et al. (2016) Notch-independent RBPJ controls angiogenesis in the adult heart. Nat Commun 7:12088
Hartley, Paul S; Motamedchaboki, Khatereh; Bodmer, Rolf et al. (2016) SPARC-Dependent Cardiomyopathy in Drosophila. Circ Cardiovasc Genet 9:119-29
Azad, Priti; Zhao, Huiwen W; Cabrales, Pedro J et al. (2016) Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease. J Exp Med 213:2729-2744
Dewan, Sukriti; McCabe, Kimberly J; Regnier, Michael et al. (2016) Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation-An Integrated Multiscale Modeling Study. J Phys Chem B 120:8264-75

Showing the most recent 10 out of 82 publications