An important function of the endothelium lining the inner surface of blood vessels is to provide a selective barrier between blood and the surrounding tissues. During the development of acute lung injury (ALI) the endothelial barrier is weakened, leading to increased permeability. It is well known that the family of small ras homology (Rho) GTPases (RhoA, Rad, Cdc42) play a crucial role in the maintenance of endothelial barrier properties. The two best-characterized members of the Rho GTPases: Rho A and Rad, appear to regulate endothelial barrier function in an antagonistic manner. Thus, the activation of Rho A impairs barrier function whereas Rad appears to support barrier integrity. In addition, our recent studies have shown that during the development of ALI in the mouse lung the activities of RhoA and Rad are regulated in an opposing manner such that RhoA activity is increased and Rad activity is attenuated. Together these changes would favor barrier disruption. However, the mechanism by which this opposing regulation occurs unresolved and is the major focus of this project. We will evaluate the mechanisms by which uncoupled eNOS leads to modulation of RhoA/Rad balance through nitration-mediated modifications. We will also determine if preventing RhoA and Rad nitration is barrier protective in vitro and reduces lung injury in both G'and G^-mouse models of ALI, in vivo. It is anticipated that this Project using state-of-the-art cellular, molecular, biochemical, and physiological approaches that will not only increase our understanding of the mechanisms by which RhoA and Rad are regulated during both G(-)- and G(+) -induced ALI but will facilitate the development of new strategies and targets for the treatment of a disease that has not seen a significant drop in mortality in 40 years.

Public Health Relevance

; The overall goal of this Project is to develop a better understanding of the mechanisms by which protein nitration alters RhoA and Rad activity in acute lung injury (ALI). Emphasis is placed on understanding both novel mechanisms and on developing novel reagents to restore EC barrier function during ALI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL101902-03
Application #
8508288
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
$347,103
Indirect Cost
$115,702
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

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