Studies have indicated that renin-angiotensin system (RAS) and reactive oxygen species (ROS) impact on , endothelial function and are involved in cardiovascular remodeling associated with hypertension, atherosclerosis and heart failure. RAS and ROS promote the expression of plasminogen activator inhibitor-1 (PAI-1), thus interrupting the balance of fibrinolysis. RAS and ROS also stimulate the expression of endothelial-leukocyte adhesion molecules and promote the adhesion of monocytes to monolayers of endothelial cells, which is the earliest detectable event in the pathogenesis of atherosclerosis. However, the molecular mechanisms of angiotensin II (Ang II) and ROS in the regulation of these genes expression are largely unknown. We have demonstrated that enzymatic activity of tyrosine phosphatase SHP-2 plays a negative role in the signal transduction of angiotensin II type-1 receptor (AT1). We also have accumulated substantial preliminary data indicating that tyrosine phosphatases SHP-2 and SHP-1 are the direct targets of ROS and may regulate ROS actions in endothelial cells. The proposed studies will test the hypothesis that tyrosine phosphatases SHP- 2 and SHP-1 play important roles in RAS- and ROS-mediated expression of PAI-1 and cell adhesion molecules in endothelial cells. Using cultured endothelial cells, we will :1) Determine the role of SHP-2 activity in Ang II-induced endothelial dysfunction; 2) Reveal mechanisms by which SHP-2 affects AT1 receptor signal transduction; and 3) Determine roles and mechanisms of SHP-1 and SHP-2 in ROS-mediated signal transduction and gene expression. The present approach, in which molecular, biochemical and cell biological methods are combined, will generate critical information regarding the roles and mechanisms of tyrosine phosphatases SHP-1 and SHP-2 in RAS- and ROS-mediated endothelial dysfunction and will lead to the identification of specific sites of intervention in the treatment of cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL069806-01
Application #
6458188
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Lin, Michael
Project Start
2001-07-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$191,998
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
City
Tyler
State
TX
Country
United States
Zip Code
75708
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