; Subjects diagnosed with ARDS exhibit ~40% mortality, thus demanding fresh approaches to the management of this serious condition. This Project will investigate a totally new mechanism of both G+ and G- bacteria-induced endothelial barrier dysfunction in human endothelial cells and in ALI/ARDS. It follows the studies on the crucial role RhoA/Rac1 imbalance in endothelial barrier dysfunction and ALI/ARSD, proposed in Project 1. Here we focus on the activation of endothelial RhoA that produces endothelial hyperpermeability in culture and increased pulmonary capillary permeability, in vivo. We propose a novel mechanism of regulating RhoA activity that could be useful in the management of ALI and ARDS. Preliminary data from Project 1 and published studies suggest that pp60src is a key step in RhoA activation, which leads to the phosphorylation of the small heat shock protein 27 (hsp27), a major cause of F-actin stress fiber formation and endothelial barrier dysfunction. The kinase, ppGOsrc is a well-known heat shock protein 90 (hsp90) client protein and we recently published that hsp27 co-immunoprecipitates with hsp90. Preliminary data suggest that the hsp90 inhibitor, 17-/ AG reduces both LPS-induced ppSOsrc activation and hsp27 phosphorylation, as well as LPS-induced RhoA activation, in endothelial cells. Furthermore, we have recently demonstrated that hsp90 inhibition prevents and reverses LPS-induced endothelial barrier dysfunction, in culture, and reduces capillary hyper-permeability, inflammation, lung dysfunction and mortality in a mouse model of LPS-induced ALI. Still, the effects of hsp90-mediated regulation of ppBOsrc, RhoA and hsp27 activation on G+ and G- induced endothelial barrier dysfunction, especially human endothelial cell barrier function, and in the management of ALI, in vivo, remain unknown. This project will test the hypothesis that hsp90 is an important regulator of human endothelial cell hyper-permeability, in vitro, and of ALI, in vivo. We will further test the hypothesis that hsp90 exerts these actions, in part, by controlling the fate of two key proteins (ppSOsrc, hsp27) that are involved in RhoA activation and signal transduction. These studies represent an exciting new possibility in the management of ALI/ARDS.

Public Health Relevance

The goal of this study is to develop new approaches to the management of acute lung injury and acute respiratory distress syndrome, conditions that carry a high degree of mortality. We propose a novel approach aimed at restoring the known dysfunction and increased permeability of lung capillary vessels.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL101902-03
Application #
8508289
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
3
Fiscal Year
2013
Total Cost
$335,580
Indirect Cost
$111,860
Name
Georgia Regents University
Department
Type
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Pati, Paramita; Fulton, David J R; Bagi, Zsolt et al. (2016) Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice. Hypertension 67:661-8
Rafikova, Olga; Meadows, Mary L; Kinchen, Jason M et al. (2016) Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung. PLoS One 11:e0150480
Fulton, David J R; Barman, Scott A (2016) Clarity on the Isoform-Specific Roles of NADPH Oxidases and NADPH Oxidase-4 in Atherosclerosis. Arterioscler Thromb Vasc Biol 36:579-81
Chen, Qiumei; Varga, Monika; Wang, Xiaoyin et al. (2016) Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction. J Am Heart Assoc 5:
de la Vega, Montserrat Rojo; Dodson, Matthew; Gross, Christine et al. (2016) Role of Nrf2 and Autophagy in Acute Lung Injury. Curr Pharmacol Rep 2:91-101
Kovacs, Laszlo; Han, Weihong; Rafikov, Ruslan et al. (2016) Activation of Calpain-2 by Mediators in Pulmonary Vascular Remodeling of Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 54:384-93
Kovacs-Kasa, Anita; Gorshkov, Boris A; Kim, Kyung-Mi et al. (2016) The protective role of MLCP-mediated ERM dephosphorylation in endotoxin-induced lung injury in vitro and in vivo. Sci Rep 6:39018
Sun, Xutong; Kellner, Manuela; Desai, Ankit A et al. (2016) Asymmetric Dimethylarginine Stimulates Akt1 Phosphorylation via Heat Shock Protein 70-Facilitated Carboxyl-Terminal Modulator Protein Degradation in Pulmonary Arterial Endothelial Cells. Am J Respir Cell Mol Biol 55:275-87
Chen, Feng; Li, Xueyi; Aquadro, Emily et al. (2016) Inhibition of histone deacetylase reduces transcription of NADPH oxidases and ROS production and ameliorates pulmonary arterial hypertension. Free Radic Biol Med 99:167-178
Romero, Maritza J; Lucas, Rudolf; Dou, Huijuan et al. (2016) Role of growth hormone-releasing hormone in dyslipidemia associated with experimental type 1 diabetes. Proc Natl Acad Sci U S A 113:1895-900

Showing the most recent 10 out of 73 publications