Allopurinol attenuates oxidative stress and cardiac fibrosis in angiotensin II-induced cardiac diastolic dysfunction.
OBJECTIVE
Oxidative stress and fibrosis is implicated in cardiac remodeling and failure. We tested whether allopurinol could decrease myocardial oxidative stress and attenuate cardiac fibrosis and left ventricular diastolic dysfunction in angiotensin II (AngII)-induced hypertensive mice.


METHODS
We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or allopurinol in daily doses, which did not lower blood pressure.


RESULTS
Allopurinol improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of cardiac fibrosis. However, allopurinol showed no effect on the increased systolic blood pressure by angiotensin II infusion. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) [GSH/GSSG] was decreased and malondialdehyde levels were increased in the hearts of AngII-treated mice. Allopurinol also inhibited both the decrease in the GSH/GSSG ratio and the increase in malondialdehyde levels in the heart. Infusion of AngII-induced upregulation of transfer growth factor (TGF)-β1, Smad3 expression and downregulation of Smad7 expression. Treatment with allopurinol reduced cardiac levels of TGF-β1, Smad3, and increased Smad7 expression.


CONCLUSIONS
These results suggest that allopurinol prevents pathological remodeling of the heart in AngII-induced hypertensive mice. The antioxidative effect of allopurinol contributes to the regression of AngII-induced cardiac diastolic dysfunction. These effects of allopurinol to prevent cardiac fibrosis are mediated at least partly through modulation of the TGF-β1/Smad signaling pathway.
Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University Medical School, Shanghai, PR China. jiananchina@hotmail.com
Nan
N
Jia
Peixin
P
Dong
Ying
Y
Ye
Cheng
C
Qian
Qiuyan
Q
Dai
D000493:Allopurinol / Q000494:pharmacology*; D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D054144:Heart Failure, Diastolic / Q000139:chemically induced / Q000517:prevention & control*; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D051785:Smad Proteins / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D000493:Allopurinol