Improvement of mechanical heart function by trimetazidine in db/db mice.
OBJECTIVE
To investigate the influence of trimetazidine, which is known to be an antioxidant and modulator of metabolism, on cardiac function and the development of diabetic cardiomyopathy in db/db mouse.


METHODS
Trimetazidine was administered to db/db mice for eight weeks. Cardiac function was measured by inserting a Millar catheter into the left ventricle, and oxidative stress and AMP-activated protein kinase (AMPK) activity in the myocardium were evaluated.


RESULTS
Untreated db/db mice exhibited a significant decrease in cardiac function compared to normal C57 mice. Oxidative stress and lipid deposition were markedly increased in the myocardium, concomitant with inactivation of AMPK and increased expression of peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1 alpha). Trimetazidine significantly improved systolic and diastolic function in hearts of db/db mice and led to reduced production of reactive oxygen species and deposition of fatty acid in cardiomyocytes. Trimetazidine also caused AMPK activation and reduced PGC-1 alpha expression in the hearts of db/db mice.


CONCLUSIONS
The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1 alpha were involved in this process. Furthermore, our study suggests that trimetazidine suppresses the development of diabetic cardiomyopathy, which warrants further clinical investigation.
Li
Yuan-jing
YJ
Department of Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.
Wang
Pei-hua
PH
Chen
Chen
C
Zou
Ming-hui
MH
Wang
Dao-wen
DW
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D048909:Diabetes Complications / Q000188:drug therapy*; D003920:Diabetes Mellitus / Q000378:metabolism*; D005223:Fats / Q000032:analysis / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood; D014292:Trimetazidine / Q000494:pharmacology / Q000627:therapeutic use*
D000975:Antioxidants; D005223:Fats; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D055372:AMP-Activated Protein Kinases; D014292:Trimetazidine
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