Trimetazidine inhibits pressure overload-induced cardiac fibrosis through NADPH oxidase-ROS-CTGF pathway.
OBJECTIVE
Cardiac fibrosis contributes to the transition from compensated ventricular hypertrophy to heart failure, which can be promoted by connective tissue growth factor (CTGF). Trimetazidine (TMZ), an anti-angina drug, also has benefits in non-ischaemic heart disease. We wondered whether TMZ has an effect on cardiac fibrosis from pressure overload by downregulating CTGF.


RESULTS
Male Sprague-Dawley rats underwent transverse aortic constriction (TAC) or sham operation and then after 20 weeks were assigned to receive TMZ or saline for another 5 weeks. TMZ significantly inhibited collagen accumulation, CTGF expression, and reactive oxygen species (ROS) production induced by TAC. Furthermore, the effects of TMZ on ROS, the upstream signal of CTGF synthesis signal transduction, were evaluated in cardiac fibroblasts. The result showed that the ROS level was reduced by TMZ on stimulation with angiotensin II. Additionally, the NADPH oxidase activity was ameliorated with TMZ by the regulation of translocation of its subunit Rac1.


CONCLUSIONS
TMZ effectively inhibits myocardial fibrosis, perhaps through the NADPH oxidase-ROS-CTGF signalling pathway. Our findings may be used to provide new clues for the potential function of TMZ in pressure overload-induced myocardial fibrosis.
Liu
Xuehui
X
Department of Cardiology, Institute of Vascular Medicine, Peking University, Beijing, People's Republic of China.
Gai
Yingli
Y
Liu
Fei
F
Gao
Wei
W
Zhang
Youyi
Y
Xu
Ming
M
Li
Zhaoping
Z
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
C526316:CCN2 protein, rat; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D008315:Malondialdehyde; D003094:Collagen; D019255:NADPH Oxidases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D014292:Trimetazidine