title: Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat.
abstract: Angiotensin II (ANG II) contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. ANG II stimulation of the ANG type 1 receptor (AT(1)R) generates reactive oxygen species via NADPH oxidase, which facilitates this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo AT(1)R blockade (AT(1)B) (valsartan) or superoxide dismutase/catalase mimetic (tempol) treatment in a rodent model of chronically elevated tissue levels of ANG II, the transgenic (mRen2) 27 rat (Ren2). Ren2 rats overexpress the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6-7 wk old) male Ren2 and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Heart tissue NADPH oxidase (NOX) activity and immunohistochemical analysis of subunits NOX2, Rac1, and p22(phox), heart tissue malondialdehyde, and insulin-stimulated protein kinase B (Akt) activation were measured. Structural changes were assessed with cine MRI, transmission electron microscopy, and light microscopy. Increases in septal wall thickness and altered systolic function (cine MRI) were associated with perivascular fibrosis and increased mitochondria in Ren2 on light and transmission electron microscopy (P < 0.05). AT(1)B, but not tempol, reduced blood pressure (P < 0.05); significant improvements were seen with both AT(1)B and tempol on NOX activity, subunit expression, malondialdehyde, and insulin-mediated activation/phosphorylation of Akt (each P < 0.05). Collectively, these data suggest cardiac oxidative stress-induced structural and functional changes are driven, in part, by AT(1)R-mediated increases in NADPH oxidase activity.
authors: University of Missouri--Columbia School of Medicine, Division of Nephrology, MA436, DC043.0, One Hospital Dr., Columbia, MO 65212, USA. whaleyconnella@health.missouri.edu
authors: Adam
authors: A
authors: Whaley-Connell
authors: Gurushankar
authors: G
authors: Govindarajan
authors: Javad
authors: J
authors: Habibi
authors: Melvin R
authors: MR
authors: Hayden
authors: Shawna A
authors: SA
authors: Cooper
authors: Yongzhong
authors: Y
authors: Wei
authors: Lixin
authors: L
authors: Ma
authors: Mahnaz
authors: M
authors: Qazi
authors: Daniel
authors: D
authors: Link
authors: Poorna R
authors: PR
authors: Karuparthi
authors: Craig
authors: C
authors: Stump
authors: Carlos
authors: C
authors: Ferrario
authors: James R
authors: JR
authors: Sowers
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008929:Mitochondria, Heart / Q000648:ultrastructure; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D013113:Spin Labels; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D003497:Cyclic N-Oxides; D021122:Protein Subunits; D013113:Spin Labels; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin; D014633:Valine; C001803:tempol