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1 Internal Medicine, Division of Nephrology, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
2 Internal Medicine, Division of Cardiology, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
3 Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
4 Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States; Columbia, Missouri, United States
5 Diabetes Center, University of Arizona, Tuscon, Arizona, United States
6 Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
7 Internal Medicine, Division of Endocrinology, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
* To whom correspondence should be addressed. E-mail: whaleyconnella{at}health.missouri.edu.
Angiotensin-II (Ang-II) contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Ang-II stimulation of the Ang type 1 receptor (AT1R) generates reactive oxygen species (ROS) 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 AT1R blockade (AT1B) (valsartan) or superoxide dismutase (SOD)/catalase mimetic (tempol) treatment in a rodent model of chronically elevated tissue levels of Ang-II, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6-7 week old) male Ren2 and age-matched Sprague-Dawley (SD) rats were treated with valsartan (Ren2-V; 30 mg/kg), tempol (Ren2-T; 1 mmol/L), or placebo for three weeks. Heart tissue NADPH oxidase (NOX) activity and immunohistochemical (IHC) analysis of subunits NOX2, Rac1, and p22phox, heart tissue malondialdehyde (MDA), and insulin stimulated protein kinase B-(Akt) activation were measured. Structural changes were assessed with cine MRI, transmission electron microscopy (TEM), 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 TEM (p<0.05). AT1B, but not tempol, reduced blood pressure (p<0.05); significant improvements were seen with both AT1B and tempol on NOX activity, subunit expression, MDA, 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 AT1R-mediated increases in NADPH oxidase activity.
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