Angiotensin I (Ang I) can be processed into a number of active fragments, of which Ang II remains the most widely studied. We have shown that Ang I can be processed directly into another unique product- Ang-(1-7)-which possesses important actions that include vasodilation, diuresis and natriuresis, stimulation of prostaglandins, potentiation of the vasodilator effects of bradykinin and the release of nitric oxide. These actions of Ang-(1-7) and the lack of vasoconstrictor, sodium and water retaining effects associated with Ang II argue that the production of Ang-(1-7) may counter-balance the actions of Ang II. In support of this hypothesis, we find that inhibition of Ang-(1-7) synthesis form Ang I results in a hypertensive response that is particularly revealed in animals that are salt depleted or under chronic blockade of the renin- angiotensin system (RAS). Moreover, we show that neutral endopeptidase or neprilysin (NEP) and angiotensin-converting enzyme (ACE) may be the predominant enzymes that generate and metabolize Ang-(1-7). The primary objective of this proposal will be to determine how activation of the RAS leads to variable expression of Ang-(1-7).
The aims of this proposal are based on the hypothesis that regulation of NEP and ACE will influence the vascular levels of Ang (1-7) to oppose the actions of Ang II. We propose that under conditions such as low salt NEP is up- regulated to increase the generation of Ang-(1-7) while reciprocal changes in ACE also influence the peptide through a degradative process.
Specific Aim 1 will establish the kinetic characterization of the processing of Ang I and Ang-(1-7) by ACE and NEP.
Specific Aim 2 will explore the regulation of NEP and ACE under reduced salt intake in normotensive and hypertensive animals.
Specific Aim 3 will investigate the mechanisms of the regulation of NEP and ACE in aortic endothelial cells. The proposed studies will provide a new understanding of the regulation of the biochemical processes that control expression of the components of the RAS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL051952-09
Application #
6573084
Study Section
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
9
Fiscal Year
2002
Total Cost
$131,864
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
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Ola, Mohammad Shamsul; Alhomida, Abdullah S; Ferrario, Carlos M et al. (2017) Role of Tissue Renin-angiotensin System and the Chymase/angiotensin-( 1-12) Axis in the Pathogenesis of Diabetic Retinopathy. Curr Med Chem 24:3104-3114
Ferrario, Carlos M; Mullick, Adam E (2017) Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol Res 125:57-71
Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:

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