Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling.
The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine, and NADPH oxidase (NOX) subunits (gp91(phox) recently renamed NOX2, p22(phox), Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.
Stas
Sameer
S
Division of Endocrinology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA.
Whaley-Connell
Adam
A
Habibi
Javad
J
Appesh
Lama
L
Hayden
Melvin R
MR
Karuparthi
Poorna R
PR
Qazi
Mahnaz
M
Morris
E Matthew
EM
Cooper
Shawna A
SA
Link
C Daniel
CD
Stump
Craig
C
Hay
Meredith
M
Ferrario
Carlos
C
Sowers
James R
JR
D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D005355:Fibrosis; D008279:Magnetic Resonance Imaging; D008297:Male; D046529:Microscopy, Electron, Transmission; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; C473112:Ren2 protein, mouse; D013148:Spironolactone; D019255:NADPH Oxidases; D012083:Renin