A large portion of the population is afflicted by the hypertensive and cardiovascular degenerative effects of AII. Because plasma levels of AII are often normal in the above disease states, abnormalities are likely to exist in receptor regulation and/or cell signaling, the mechanisms of which are complex and not fully understood. The applicant will use vascular smooth muscle cells in culture to i) define the C-terminal domain responsible for activation of phospholipase C; ii) investigate and identify the mechanisms of cross-talk by which the G-protein-coupled receptor activates MAPkinase via calcium calmodulin kinase; iii) identify receptor binding proteins responsible for receptor internalization and the mechanism of desensitization; and iv) down regulation of the AT1 mRNA by destabilization of the mRNA. The focus is on the dominant vasoconstrictor, mitogenic, hypertrophic receptor (AT1) and the regulatory function of the cytosolic C-terminal region. Techniques to be used include receptor antibodies, AT1 engineered mutant, the yeast two hybrid system, and specific new inhibitors and assay techniques. The approach using cellular and molecular tools will provide significant new information on complex receptor regulation and signaling and thus insights into potential defects in and therapy for various vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL058205-01
Application #
2031409
Study Section
Special Emphasis Panel (ZRG4-CVB (03))
Project Start
1997-04-10
Project End
2001-03-31
Budget Start
1997-04-10
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
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
Samuel, Preethi; Khan, Mohammad Azhar; Nag, Sourashish et al. (2013) Angiotensin AT(2) receptor contributes towards gender bias in weight gain. PLoS One 8:e48425
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
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
Senbonmatsu, Takaaki; Iida, Shinichiro; Yoshikawa, Ayumu et al. (2010) New perspectives on secretion of (pro)renin receptor into extracellular space. Front Biosci (Elite Ed) 2:1362-7

Showing the most recent 10 out of 77 publications