Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats.
Angiotensin-II (Ang-II)-stimulated increases in nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and oxidative stress are known to play a key role in cardiac remodeling. Inhibition of isoprenylation and activation of small G proteins, such as Rac1, a component of NADPH oxidase, may mediate the antioxidant actions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). In this study, we investigated the effects of rosuvastatin on cardiac oxidative stress and remodeling in transgenic rats (Ren2) overexpressing the mouse renin gene with elevated cardiac levels of Ang-II. We treated 6- to 7-wk-old Ren2 rats and age-matched Sprague-Dawley (SD) rats with rosuvastatin (10 mg/kg.d) or vehicle for 3 wk. At the end of the treatment period, left ventricular mass, wall thickness, ejection fraction (by echocardiography), and cardiac remodeling (by light microscopy and immunohistochemistry) were assessed. In addition, myocardial content of nitrotyrosine, malondialdehyde, NADPH-oxidase subunits (gp91(phox), p40(phox), and p22(phox)), and Rac1 were analyzed by immunochemistry. Systolic blood pressure was significantly higher in Ren2 rats, compared with SD rats (P < 0.05); rosuvastatin had no significant effect on systolic blood pressure in either group. In Ren2, but not SD rats, rosuvastatin significantly improved the ventricular ejection fraction, cardiac hypertrophy, and perivascular fibrosis (P < 0.05). In addition, rosuvastatin administration significantly decreased the accentuated myocardial gp91(phox), p40(phox), p22(phox), and Rac1 expression. These changes were accompanied by a parallel reduction in myocardial lipid peroxidation (nitrotyrosine and malondialdehyde content) (P < 0.05). These results suggest that in vivo statin treatment through its direct actions on the heart reduces oxidative stress and remodeling including ventricular mass regression in the Ang-II-dependent Ren2 model.
Habibi
Javad
J
University of Missouri School of Medicine, Columbia, Missouri 65212, USA.
Whaley-Connell
Adam
A
Qazi
Mahnaz A
MA
Hayden
Melvin R
MR
Cooper
Shawna A
SA
Tramontano
Anthony
A
Thyfault
John
J
Stump
Craig
C
Ferrario
Carlos
C
Muniyappa
Ranganath
R
Sowers
James R
JR
D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D005260:Female; D005355:Fibrosis; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010750:Phosphoproteins / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D015415:Biomarkers; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D011743:Pyrimidines; C473112:Ren2 protein, mouse; D013449:Sulfonamides; C085072:neutrophil cytosol factor 40K; D000068718:Rosuvastatin Calcium; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D012083:Renin; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein