Improvement of mechanical heart function by trimetazidine in db/db mice

Abstract

Aim: 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-1α (PGC-1α). 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-1α expression in the hearts of db/db mice. Conclusion: 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-1α were involved in this process. Furthermore, our study suggests that trimetazidine suppresses the development of diabetic cardiomyopathy, which warrants further clinical investigation.

Cardiac metabolism — A promising therapeutic target for heart failure

“…Trimetazidine works by inhibiting the LC 3-KAT enzyme of the β-oxidation pathway (Kantor, et al, 2000), but also has weak inhibitory effects on CPT1 (Lee, et al, 2004). An experimental study in mice with diabetic cardiomyopathy demonstrated improvements in both systolic and diastolic function following trimetazidine treatment, as well as a reduction in ROS and improvement in cardiac energetic status (Li, et al, 2010). Clinical studies in man have also supported the beneficial effects of trimetazidine.…”

Mechanisms of Lipotoxicity in the Cardiovascular System

“…This effect of adiponectin likely increases complete oxidation of fatty acids and limits the likelihood that toxic lipid intermediates will accumulate. Trimetazidine, an inhibitor of long-chain 3-ketoacyl coenzyme A thiolase activates AMPK, reduces lipid accumulation, and restores contractile function in db/db diabetic mice [64]. The mechanism of action of trimetazidine also involves amelioration of oxidative stress via increased antioxidant defenses, such as MnSOD.…”

The prevalence of trimetazidine use in athletes in Poland: excretion study after oral drug administration

“…Moreover, the use of high TMZ doses leads to the maintenance of electrolyte homeostasis in myocardium by protecting the cardiac cells from the accumulation of calcium and sodium ions in ischemic hearts . It is also known that long‐term treatment with TMZ alleviates the myocardial accumulation of the oxidation reactive form and prevents lipid per‐oxidation . It improves the activity of the superoxide dismutase (an antioxidant enzyme) and relieves the oxidative stress phenomena .…”