Contribution of different Nox homologues to cardiac remodeling in two-kidney two-clip renovascular hypertensive rats: effect of valsartan.
Growing evidences have shown that hypertension, cardiac hypertrophy and fibrosis were associated with an overactivity of NAD(P)H oxidase. It is unknown, however, which isoform of NAD(P)H oxidase yields O(2)*(-) formation in heart and aorta in two-kidney, two-clip (2K2C) hypertensive rats in vivo and thus is responsible for the development of cardiac remodeling. We examined the pathological change of NAD(P)H oxidase homologues and tested the effect of valsartan on the cardiac remodeling in 2K2C renovascular hypertensive rats. Four weeks after male Sprague-Dawley rats accepted 2K2C or sham operation, 2K2C hypertensive (>160 mmHg) rats were divided into vehicle-treated (2K2C) and valsartan (30 mg kg(-1) per day, for 6 weeks)-treated (2K2C+Val) groups, which were compared with sham-operated controls (Sham). At week 10, 2K2C hypertensive rats showed increased serum level of angiotensin II (Ang II), MDA and blood pressure (BP), obvious cardiac hypertrophy and fibrosis, increased O(2)*(-) production and NAD(P)H oxidase activity and expression in aorta and heart. The heart in 2K2C hypertensive rats preferred to use NADH as substrate while the aorta used both NADH and NADPH. Valsartan treatment decreased BP, ameliorated cardiac hypertrophy and fibrosis, decreased O(2)*(-) production and NAD(P)H oxidase activity in aorta and heart. Nox2 and Nox4 protein expression increased in heart, while Nox1 and Nox4 increased in aorta in 2K2C hypertensive rats, which were all normalized after valsartan treatment. In conclusion, these data indicate that different Nox expression might account for substrate preference and the formation of O(2)*(-) by NAD(P)H oxidase resulting from elevated Ang II in the 2K2C model contributes to the development of renovascular hypertension and subsequent cardiac remodeling.
Wang
Ping
P
Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
Tang
Futian
F
Li
Ruifang
R
Zhang
Huijie
H
Chen
Shaorui
S
Liu
Peiqing
P
Huang
Heqing
H
D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D006978:Hypertension, Renovascular / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008562:Membrane Glycoproteins / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000601:surgery; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D008562:Membrane Glycoproteins; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; D008315:Malondialdehyde; D000068756:Valsartan; D009247:NADH, NADPH Oxidoreductases; C500593:Cybb protein, rat; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614712:NOX1 protein, rat; C498911:Nox4 protein, rat; C060505:neutrophil cytosolic factor 1; D014633:Valine