(Verbatim from the application): The peptide hormone angiotensin II (AngII) contributes to various cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The growth promoting activity of the AngII type-1 (AT1) receptor is implicated in the progression of cardiovascular remodeling. In vascular smooth muscle cells (VSMC), AngII is believed to transmit its growth-promoting signal through activation of tyrosine kinases (PYK2, Src, JAK, and EGF receptor). We have reported that the transactivation of the EGF receptor (EGFR) by Angli is essential for the activation of ERK and p70 S6 kinase, and subsequent c-Fos induction and protein synthesis by AngII in cultured VSMC. Thus, the EGFR transactivation could play a central role in AngII mediated vascular remodeling. Several mechanisms implicating an upstream tyrosine kinase, reactive oxygen species (ROS) and a metalloprotease-dependent generation of an EGFR ligand are proposed for the transactivation. However, a huge void remains in our knowledge in terms of the mechanism by which AngII/AT1 activates the EGFR. Also, it is not clear whether other signals such as activation of p38 and JNK MAP kinases by AngII are under control of transactivation, if they are regulated by other tyrosine kinases, or if a tyrosine phosphatase such as SHP-2 is involved. Thus, we will evaluate the hypothesis that the tyrosine kinases (PYK2 and JAK2). the tyrosine phosphatase SHP-2. ROS. and the metalloprotease ADAM regulate activation of EGFR and/or MAP kinases by AngII in VSMC.
The specific aims of this application are 1) to investigate the roles of the following factors in the EGFR transactivation mechanisms by AngII (PYK2, JAK2, ROS, metalloprotease); 2) to investigate the involvement of the tyrosine kinases in activation of p38 and JNK by AnglI; 3) to investigate the role of SHP-2 in regulation of PYK2; 4) to investigate the role of SHP-2 in regulation of MAP kinases by AngII. These studies will unravel the initial key mechanism by which vasculotrophic factors such as Angil regulate vascular remodeling. Moreover, the clarification of the indispensable hypertrophic and hyperplastic signals in combination with the identification of key enzymes (kinases and/or phosphatases) will provide potential therapeutic targets in cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37HL058205-05
Application #
6332219
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
1997-04-10
Project End
2006-03-30
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
5
Fiscal Year
2001
Total Cost
$340,032
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Faghih, Mahya; Hosseini, Sayed M; Smith, Barbara et al. (2015) Knockout of Angiotensin AT2 receptors accelerates healing but impairs quality. Aging (Albany NY) 7:1185-97
Huang, Jianbin; Yamashiro, Yoshito; Papke, Christina L et al. (2013) Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice. Sci Transl Med 5:183ra58, 1-11
Hafko, Roman; Villapol, Sonia; Nostramo, Regina et al. (2013) Commercially available angiotensin II At? receptor antibodies are nonspecific. PLoS One 8:e69234
Wang, Ning; Frank, Gerald D; Ding, Ronghua et al. (2012) Promyelocytic leukemia zinc finger protein activates GATA4 transcription and mediates cardiac hypertrophic signaling from angiotensin II receptor 2. PLoS One 7:e35632
Biswas, Kazal Boron; Nabi, Ahm Nurun; Arai, Yoshie et al. (2011) Qualitative and quantitative analyses of (pro)renin receptor in the medium of cultured human umbilical vein endothelial cells. Hypertens Res 34:735-9
Inagami, Tadashi (2011) Mitochondrial angiotensin receptors and aging. Circ Res 109:1323-4
Sun, Xiao; Iida, Shinichiro; Yoshikawa, Ayumu et al. (2011) Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely. Hypertens Res 34:701-6
Verlander, Jill W; Hong, Seongun; Pech, Vladimir et al. (2011) Angiotensin II acts through the angiotensin 1a receptor to upregulate pendrin. Am J Physiol Renal Physiol 301:F1314-25
Sakoda, Mariyo; Ichihara, Atsuhiro; Kurauchi-Mito, Asako et al. (2010) Aliskiren inhibits intracellular angiotensin II levels without affecting (pro)renin receptor signals in human podocytes. Am J Hypertens 23:575-80
Biswas, Kazal Boron; Nabi, A H M Nurun; Arai, Yoshie et al. (2010) Aliskiren binds to renin and prorenin bound to (pro)renin receptor in vitro. Hypertens Res 33:1053-9

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