Trimetazidine Attenuates Heart Failure by Improving Myocardial Metabolism via AMPK

Abstract

Energic deficiency of cardiomyocytes is a dominant cause of heart failure. An antianginal agent, trimetazidine improves the myocardial energetic supply. We presumed that trimetazidine protects the cardiomyocytes from the pressure overload-induced heart failure through improving the myocardial metabolism. C57BL/6 mice were subjected to transverse aortic constriction (TAC). After 4 weeks of TAC, heart failure was observed in mice manifested by an increased left ventricular (LV) chamber dimension, an impaired LV ejection fraction evaluated by echocardiography analysis, which were significantly restrained by the treatment of trimetazidine. Trimetazidine restored the mitochondrial morphology and function tested by cardiac transmission electron microscope and mitochondrial dynamic proteins analysis. Positron emission tomography showed that trimetazidine significantly elevated the glucose uptake in TAC mouse heart. Trimetazidine restrained the impairments of the insulin signaling in TAC mice and promoted the translocation of glucose transporter type IV (GLUT4) from the storage vesicle to membrane. However, these cardioprotective effects of trimetazidine in TAC mice were notably abolished by compound C (C.C), a specific AMPK inhibitor. The enlargement of neonatal rat cardiomyocyte induced by mechanical stretch, together with the increased expression of hypertrophy-associated proteins, mitochondria deformation and dysfunction were significantly ameliorated by trimetazidine. Trimetazidine enhanced the isolated cardiomyocyte glucose uptake in vitro. These benefits brought by trimetazidine were also removed with the presence of C.C. In conclusion, trimetazidine attenuated pressure overload-induced heart failure through improving myocardial mitochondrial function and glucose uptake via AMPK.

Pirfenidone alleviates cardiac fibrosis induced by pressure overload via inhibiting TGF‐β1/Smad3 signalling pathway

“…The mice were anaesthetised and subjected to sham or TAC surgery with a 27‐gauge needle and 7–0 silk suture as described previously. 15 Mice in the sham group and the TAC group were provided by Vehicle, PFD (300 mg/kg/day) 16 and CAP (20 mg/kg/day), 7 respectively. Vehicle, PFD, and CAP were intragastric administrated with an equal volume (200 μl).…”

“…After 1 week of adaptive feeding, the mice were randomly divided into six groups: Sham group, PFD group, CAP group, TAC group, TAC + PFD group, TAC + CAP group. The mice were anaesthetised and subjected to sham or TAC surgery with a 27‐gauge needle and 7–0 silk suture as described previously 15 . Mice in the sham group and the TAC group were provided by Vehicle, PFD (300 mg/kg/day) 16 and CAP (20 mg/kg/day), 7 respectively.…”

Mitophagy: A Potential Target for Pressure Overload-Induced Cardiac Remodelling

“…Therefore, the abnormality of the structure and function of mitochondria in the pressure overload model has been frequently investigated. In vivo and in vitro experiments have confirmed that mitochondria swell and cristae become fragmented and disordered in cardiomyocytes under pressure overload [ 7 , 8 ]. Mitophagy is a selective autophagy pathway that mediates mitochondrial quality control by scavenging damaged mitochondria and coordinating the dynamic balance between mitochondrial and cellular energy requirements [ 9 ] ( Figure 1 ).…”

Trimetazidine as a Modifier of Chemotherapy-Induced Cardiovascular Redox-Homeostasis Disturbances

“…It is known that this drug is the only cardioprotector included in the protocols for the treatment of patients with CVD, both by the Russian Society of Cardiology and the European Council of Cardiology [12,13]. TMZ inhibits the mitochondrial 3-ketoacyl-CoA thiolase, improves myocardial metabolism through enhancing the activation of AMPK, and thus improves insulin sensitivity and resultantly relived mitochondrial dysfunction [14,15].…”