Recently interest in aldosterone (ALDO) as a CV toxic hormone, beyond its well-known effects on blood pressure and ion homeostasis, has intensified. Experimental and clinical data document that ALDO is associated with cardiac hypertrophy, fibrosis, nephropathy and strokes. Thus, derangements in ALDO secretion, particularly in relation to sodium (Na) intake are an important link between CV damage and heart failure, hypertension (HBP) and/or diabetes mellitus. We have assessed this possibility by using a HBP rat model in which there is dysregulation of the vasodilator/vasoconstrictor milieu. Our preliminary results strongly support a CV toxic role for ALDO and suggest that, in part, mediators of these effects are calveolins (CAVs) located in the target cell's caveolae microdomains. Thus, the primary goal of this proposal is to determine whether ALDO mediates its effects on the heart, including CV damage, through interaction with CAVs, and if so, which CAVs are involved. ALDO's cardiotoxic effects are only manifested in the presence of a liberal Na intake. Thus, in vivo models are required. To accomplish these goals, we will expand our extensive studies in rats to mice. We will study normal (wild type) mice and three mouse strains--each one with a different CAV knocked out. We will use three perturbations: chronic modulation of ALDO levels physiologically by changing dietary salt; acute administration of ALDO; and L-NAME/AngII to induce cardiac damage. Finally, we will use gene and protein arrays to identify genes and proteins whose regulation is altered by ALDO in the presence of dietary Na. Techniques that will be used include whole organism physiology, telemetry, real time RT-PCR, immuno-precipitation, confocal microscopy, expression cloning using chip technology and proteomics. Our results should better define the rationale for the use of mineralocorticoid receptor antagonists to prevent damage to the heart and other tissues when ALDO levels are inappropriate relative to Na intake.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069208-02
Application #
6745133
Study Section
Special Emphasis Panel (ZRG1-CVB (03))
Program Officer
Barouch, Winifred
Project Start
2003-05-01
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$448,225
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Tan, Jia W; Gupta, Tina; Manosroi, Worapaka et al. (2017) Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variants. JCI Insight 2:
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