The current proposal identifies a novel hormonally regulated S-nitrosylation/denitrosylation coupling loop in the pulmonary vascular endothelium. This feedback loop consists of eNOS, which is up-regulated by estrogens, and GSNO-R, which is down-regulated by androgens. These two proteins physically interact, however the impact of this interaction on pulmonary physiology and pathology is unknown. Thus, defining the subcellular location of this interaction within the endothelial cell and the influence of this relationship on local S-nitrosothiol (SNO) abundance is of paramount importance to identifying its role in normal pulmonary vascular physiology and pathology. SNOs have been implicated in the development of various pulmonary diseases, many of which display distinct gender preferences in presentation or a change in severity at puberty by unknown mechanisms. In this respect, estrogen increases SNO formation causing a compensatory increase in GSNO-R activity. Thus, increased pulmonary vascular endothelial SNO exposure without increases in GSNO-R activity, which is abnormal in male mice exposed to exogenous SNOs, produces SNO toxicity including pulmonary vascular remodeling and PH. Thus, abnormalities in GSNO-R may diminish protection of pulmonary vascular endothelium to increased eNOS activity, resulting in increased risk to develop PH. We hypothesize that SNO bioavailability in the endothelium is regulated by a hormonally regulated S-nitrosylation/denitrosylation coupling loop. This regulatory loop may be involved in the regulation of eNOS activity and SNO bioavailability within the vascular endothelium Moreover, disruption of this regulatory loop plays a role in the gender divergence seen in PH. Three hypotheses will be examined.
Aim 1 : GSNO-R and eNOS crosstalk exists within the pulmonary endothelium.
Aim 2 : Subcellular location of eNOS/GSNO-R interaction contributes to local SNO bioavailability.
Aim 3 : Disruption of this S-nitrosylation/denitrosylation regulatory loop contributes to the gender discordance seen in PH. In summary, defining the importance of the hormonal regulation of this coupling loop and its relationship to gender susceptibility of pulmonary vascular disease will enhance our knowledge on the mechanisms of male/female mediated susceptibility/protection to disease and will increase the potential to develop gender specific therapeutic agents.

Public Health Relevance

S-nitrosothiol bioactivities may play an important role in the gender discordance seen in pulmonary diseases such as asthma and pulmonary hypertension. Hormone regulated S-nitrosylation/denitrosylation regulates the activity of endothelial nitric oxide synthase and S-nitrosoglutathione reductase determining local Snitrosothiol abundance. Defining the location of this interaction and the proteins involved may lead to new therapeutic targets in the treatment of these diseases.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL101871-05
Application #
8646969
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
Gaston, Benjamin; May, Walter J; Sullivan, Spencer et al. (2014) Essential role of hemoglobin beta-93-cysteine in posthypoxia facilitation of breathing in conscious mice. J Appl Physiol (1985) 116:1290-9
Davisson, Robin L; Bates, James N; Johnson, Alan Kim et al. (2014) Effects of intracerebroventricular injections of 5-HT on systemic vascular resistances of conscious rats. Microvasc Res 95:116-23
Zaman, Khalequz; Bennett, Deric; Fraser-Butler, Maya et al. (2014) S-Nitrosothiols increases cystic fibrosis transmembrane regulator expression and maturation in the cell surface. Biochem Biophys Res Commun 443:1257-62
Getsy, Paulina M; Davis, Jesse; Coffee, Gregory A et al. (2014) Enhanced non-eupneic breathing following hypoxic, hypercapnic or hypoxic-hypercapnic gas challenges in conscious mice. Respir Physiol Neurobiol 204:147-59
Mendoza, James P; Passafaro, Rachael J; Baby, Santhosh M et al. (2014) Role of nitric oxide-containing factors in the ventilatory and cardiovascular responses elicited by hypoxic challenge in isoflurane-anesthetized rats. J Appl Physiol (1985) 116:1371-81
Palmer, Lisa A; May, Walter J; deRonde, Kimberly et al. (2013) Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase. Respir Physiol Neurobiol 185:571-81
Sun, Yuansheng; Rombola, Christina; Jyothikumar, Vinod et al. (2013) Forster resonance energy transfer microscopy and spectroscopy for localizing protein-protein interactions in living cells. Cytometry A 83:780-93
Palmer, Lisa A; May, Walter J; deRonde, Kimberly et al. (2013) Hypoxia-induced ventilatory responses in conscious mice: gender differences in ventilatory roll-off and facilitation. Respir Physiol Neurobiol 185:497-505
Jyothikumar, Vinod; Sun, Yuansheng; Periasamy, Ammasi (2013) Investigation of tryptophan-NADH interactions in live human cells using three-photon fluorescence lifetime imaging and Forster resonance energy transfer microscopy. J Biomed Opt 18:060501
Marozkina, Nadzeya V; Wei, Christina; Yemen, Sean et al. (2012) S-nitrosoglutathione reductase in human lung cancer. Am J Respir Cell Mol Biol 46:63-70

Showing the most recent 10 out of 12 publications