Hypertension, a major public health problem afflicting more than 15% of the population, is the most significant risk factor in cardiovascular disease and major cause of heart failure, kidney failure and stroke. Since the renin-angiotensin system (RAS) plays a central role in salt and water homeostasis and the maintenance of vascular tone, each component of this system represents a potential candidate in the etiology of hypertension. This proposal will focus on the angiotensin II (Ang II) receptor, a component of the RAS, since these cell-surface receptors are responsible for mediating Ang II physiological effects. Recently, it was demonstrated that Ang 11 interacts with two pharmacologically distinct subtypes of Ang II receptors, AT1 and AT2. The complete characterization of the structural and biochemical properties of the AT1 and AT2 receptors and their genes is essential for the full understanding of the regulatory actions of Ang II and the potential role of these receptors in the pathogenesis of hypertension as well as other cardiovascular disorders. Currently, very little is known about the human AT1 and AT2 receptors (hAT1R and hAT2R) genes or how they are transcriptionally regulated and why multiple alternatively spliced mRNA transcripts are synthesized. Furthermore, little is known about the function or the signal transduction mechanism(s) of the hAT2R. Therefore, the long term goals of this project are to characterize the hAT1R and hAT2R genes and to investigate the molecular mechanisms that regulate the expression of these genes and to characterize the biochemical properties of the hAT2R.
The specific aims of this proposal are to: 1) Define the cis-regulatory mechanisms involved in selectively directing the transcription of the hAT1R and hAT2R genes by utilizing DNA-mediated gene transfer, 2) Test the hypothesis that the four distinct hAT1R mRNAs are differentially expressed, 3) Test the hypothesis that the four distinct hAT1R mRNA transcripts are translated with differential efficiencies in vitro and in vivo, 4) Test the hypothesis that hAT1R mRNAs which harbor exon 3 encode a novel hAT1R, and 5) Utilize the yeast two-hybrid system to investigate hAT2R signal transduction mechanism(s).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL048848-06
Application #
2028781
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1992-08-01
Project End
2001-07-31
Budget Start
1997-08-15
Budget End
1998-07-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Brigham Young University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Provo
State
UT
Country
United States
Zip Code
84602
Elton, Terry S; Martin, Mickey M; Sansom, Sarah E et al. (2011) miRNAs got rhythm. Life Sci 88:373-83
Belevych, Andriy E; Sansom, Sarah E; Terentyeva, Radmila et al. (2011) MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PLoS One 6:e28324
Nishijima, Yoshinori; Sridhar, Arun; Bonilla, Ingrid et al. (2011) Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology. Cardiovasc Res 91:71-9
Feldman, David; Elton, Terry S; Menachemi, Doron M et al. (2010) Heart rate control with adrenergic blockade: clinical outcomes in cardiovascular medicine. Vasc Health Risk Manag 6:387-97
Kuhn, Donald E; Nuovo, Gerard J; Terry Jr, Alvin V et al. (2010) Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains. J Biol Chem 285:1529-43
Elton, Terry S; Sansom, Sarah E; Martin, Mickey M (2010) Trisomy-21 gene dosage over-expression of miRNAs results in the haploinsufficiency of specific target proteins. RNA Biol 7:540-7
Sansom, Sarah E; Nuovo, Gerard J; Martin, Mickey M et al. (2010) miR-802 regulates human angiotensin II type 1 receptor expression in intestinal epithelial C2BBe1 cells. Am J Physiol Gastrointest Liver Physiol 299:G632-42
Terentyev, Dmitry; Belevych, Andriy E; Terentyeva, Radmila et al. (2009) miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res 104:514-21
Nuovo, Gerard J; Elton, Terry S; Nana-Sinkam, Patrick et al. (2009) A methodology for the combined in situ analyses of the precursor and mature forms of microRNAs and correlation with their putative targets. Nat Protoc 4:107-15
Wexler, Randell K; Elton, Terry; Pleister, Adam et al. (2009) Cardiomyopathy: an overview. Am Fam Physician 79:778-84

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