NADPH oxidase inhibition ameliorates cardiac dysfunction in rabbits with heart failure.
Increased NADPH oxidase activity is found in both experimental and clinical HF. Here, we investigated the effects and mechanisms of NADPH oxidase inhibition on cardiac function in rabbits with HF. HF was induced by combined volume and pressure overload. Rabbits with HF or sham operation were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for 8 weeks. Echocardiography was performed to examine the cardiac function and structure of the rabbits. Cardiac fibrosis was evaluated by masson's trichrome staining. The transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) expression were measured by real-time PCR. The expression of SERCA2a and phospholamban (PLB) was detected by reverse transcription-polymerase chain reaction and Western Blot. SERCA2a activity was evaluated by measuring the Pi liberated from ATP hydrolysis. Rabbits with HF exhibited cardiac dysfunction and fibrosis. These changes were associated with significant increases in myocardial NADPH oxidase activity and oxidative stress. Compared with sham-operated rabbits, the TGF-β, CTGF, MMP-2, and MMP-9 mRNA expression significantly increased, the expression of SERCA2a and PLB dramatically decreased, and the SERCA2a activity was lower in HF rabbits. Apocynin reduced NADPH oxidase activity and oxidative stress, decreased TGF-β, CTGF, MMP-2, and MMP-9 expression, attenuated cardiac fibrosis, increased SERCA2a and PLB expression, restored SERCA2a activity, and thereby ameliorated cardiac dysfunction. Thus, chronic NADPH oxidase inhibition ameliorated cardiac dysfunction by decreasing cardiac fibrosis and preserving SERCA2a expression and activity.
Liu
Yu
Y
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province,People's Republic of China.
Huang
He
H
Xia
Wenfang
W
Tang
Yanhong
Y
Li
Haitao
H
Huang
Congxin
C
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers; D004452:Echocardiography; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress; D010919:Placebos; D016133:Polymerase Chain Reaction; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D000098:Acetophenones; D017931:DNA Primers; D010919:Placebos; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D008315:Malondialdehyde; C056165:acetovanillone; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases