Abstract
Objective
Strategies that block angiotensin II actions on its angiotensin type 1 receptor or
inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and
interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine
if combination of direct renin inhibition with angiotensin type 1 receptor blockade
in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone
would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater
extent than either intervention alone.
Materials/Methods
We utilized the transgenic Ren2 rat which manifests increased tissue expression of
murine renin which, in turn, results in increased renin–angiotensin system activity,
aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren,
valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days.
Results
Compared to Sprague–Dawley controls, Ren2 rats displayed increased systolic blood
pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial
fibrosis and ultrastructural remodeling. These biochemical and functional alterations
were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine
content along with increases in mammalian target of rapamycin and reductions in protein
kinase B phosphorylation. Combination therapy contributed to greater reductions in
systolic blood pressure and serum aldosterone but did not result in greater improvement
in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond
either intervention alone.
Conclusions
Thereby, our data suggest that the greater impact of combination therapy on reductions
in aldosterone does not translate into greater reductions in myocardial fibrosis or
hypertrophy in this transgenic model of tissue renin overexpression.
Abbreviations:
Angt II (angiotensin II), ACE (angiotensin-converting enzyme), AT1R (Ang II type 1 receptor), EF (ejection fraction), FS (fractional shortening), HPA (heme-pomatia agglutinin), LV (left ventricular), LVID (LV internal diameter), mTOR (mammalian target of rapamycin), MR (mineralocorticoid receptor), GalNAc (N-acetylgalactosamine), PWT (posterior wall thicknesses), ROS (reactive oxygen species), RWT (relative wall thickness), RAS (renin–angiotensin system), RAAS (renin–angiotensin–aldosterone system), SWT (septal wall thicknesses), SD (Sprague–Dawley), SBP (systolic blood pressure), 3-NT (3-nitrotyrosine), Ren2 (transgenic TG(mRen2)27 rat), VVG (Verhoeff van Gieson)Keywords
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Article info
Publication history
Published online: January 28, 2013
Accepted:
December 19,
2012
Received:
September 26,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
