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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References
- The emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension.Ann Intern Med. 2009; 150: 776-783
- Hypertension in cardiovascular and kidney disease.Cardiorenal Med. 2011; 1: 183-192
- NT-proBNP, echocardiographic abnormalities and subclinical coronary artery disease in high risk type 2 diabetic patients.Cardiovasc Diabetol. 2012; 11: 19
- Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design.Nephrol Dial Transplant. 2009; 24: 1663-1671
- The impact of over-nutrition on insulin metabolic signaling in the heart and the kidney.Cardiorenal Med. 2011; 1: 102-112
- Renin–angiotensin system involvement in pressure-overload cardiac hypertrophy in rats.Am J Physiol. 1990; 259: H324-H332
- Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice.Circulation. 2002; 105: 293-296
- Mechanical stretch and angiotensin II differentially upregulate the renin–angiotensin system in cardiac myocytes in vitro.Circ Res. 1999; 85: 137-146
- Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype.Circ Res. 1993; 73: 413-423
- Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro.Cell. 1993; 75: 977-984
- Aldosterone-induced inflammation in the rat heart: role of oxidative stress.Am J Pathol. 2002; 161: 1773-1781
- Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways.J Mol Cell Cardiol. 2012; 52: 493-501
- Akt signaling mediates postnatal heart growth in response to insulin and nutritional status.J Biol Chem. 2002; 277: 37670-37677
- The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats.Br J Pharmacol. 2004; 141: 105-113
- Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease.J Renin Angiotensin Aldosterone Syst. 2003; 4: 51-61
- AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase.Hypertension. 2003; 42: 206-212
- Pressure-independent effects of angiotensin II on hypertensive myocardial fibrosis.Hypertension. 2004; 43: 499-503
- Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat.Am J Physiol Endocrinol Metab. 2007; 293: E355-E363
- Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions.J Hypertens. 2008; 26: 1453-1462
- The incidence and implications of aldosterone breakthrough.Nat Clin Pract Nephrol. 2007; 3: 486-492
- Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system.Hypertension. 1998; 32: 387-392
- Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals.Clin J Am Soc Nephrol. 2007; 2: 947-955
- Combination direct renin inhibition with angiotensin type 1 receptor blockade improves aldosterone but does not improve kidney injury in the transgenic Ren2 rat.Regul Pept. 2012; 176: 36-44
- Restoration of the blood pressure circadian rhythm by direct renin inhibition and blockade of angiotensin II receptors in mRen2.Lewis hypertensive rats.Ther Adv Cardiovasc Dis. 2012; 6: 15-29
- Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin–angiotensin–aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling.Endocrinology. 2007; 148: 3773-3780
- Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase.FASEB J. 2006; 20: 1546-1548
- Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone.Circulation. 2004; 109: 2213-2220
- Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart.Endocrinology. 2002; 143: 4828-4836
- Zonal distribution and regulation of adrenal renin in a transgenic model of hypertension in the rat.Endocrinology. 1992; 131: 1955-1962
- Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats.Hypertension. 2008; 52: 130-136
- Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents.Exp Physiol. 2008; 93: 557-563
- Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat.Am J Physiol Heart Circ Physiol. 2011; 300: H181-1890
- Effect of renininhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat.Am J Physiol Endocrinol Metab. 2008; 295: E103-E109
- Recommendations for quantification of Doppler echocardiography: a report from the Doppler quantification task force of the nomenclature and standards committee of the American Society of Echocardiography.J Am Soc Echocardiogr. 2002; 15: 167-184
- Echocardiographic characterization of the cardiovascular phenotype in rodent models.Toxicol Pathol. 2006; 34: 105-110
- Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex.Science. 2005; 307: 1098-1101
- Redox regulation of the nutrient-sensitive raptor–mTOR pathway and complex.J Biol Chem. 2005; 280: 39505-39509
http://www.novartis.com/newsroom/media-releases/en/2011/1572562.shtml. Accessed 12–2–12.
- Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone.J Mol Cell Cardiol. 1994; 26: 809-820
- Role of oxidative stress in myocardial hypertrophy and failure.J Mol Cell Cardiol. 2002; 34: 379-388
- Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of AngII myocardial fibrosis.Hypertens Res. 2012; 35: 449-456
- Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy.Hypertension. 1997; 30: 383-391
- Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signaling pathway.Basic Res Cardiol. 2009; 104: 653-667
- Ang II activates effectors of mTOR via PI3-K signaling in human coronary smooth muscle cells.Am J Physiol Heart Circ Physiol. 2004; 287: H1232-H1238
- Redox regulation of the nutrient-sensitive raptor–mTOR pathway and complex.J Biol Chem. 2004; 279: 39505-39509
- Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade.Mol Cancer Ther. 2005; 4: 1533-1540
- Local angiotensin II aggravates cardiac remodeling in hypertension.Am J Physiol Heart Circ Physiol. 2010; 299: H1328-H1338
- Additive improvement of left ventricular remodeling by aldosterone receptor blockade with eplerenone and angiotensin II type 1 receptor antagonist in rats with myocardial infarction.Nihon Yakurigaku Zasshi. 2004; 124: 83-89
- Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction.J Am Coll Cardiol. 2003; 42: 1666-1673
- Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction.Cardiovasc Res. 2005; 67: 97-105
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.