Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway

Abstract

Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated.Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms.Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2–10 μM) or SU and TMZ (40–120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested.Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] − 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC50 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (p < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP − 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (p < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo (p < 0.001) and in vitro (p < 0.05).Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.

Cardiotoxic effects of angiogenesis inhibitors

“…In mice treated with sunitinib, trimetazidine reverses cardiotoxicity and improves cardiomyocyte viability via activation of the AMPK/mTOR/ribosome S6 kinase/autophagy pathway [ 111–113 ]. Trimetazidine selectively inhibits mitochondrial long chain 3-ketoacyl-CoA thiolase, which in turn inhibits β-oxidation of fatty acids, promoting glucose utilisation and improving cardiac energy metabolism [ 114 ].…”

Trimetazidine in Heart Failure

“…Indeed, administration of trimetazidine in diabetic cardiomyopathy rats was shown to enhance cardiomyocyte autophagy and improve cardiac function ( Zhang et al, 2016 ). In addition, by promoting autophagy, trimetazidine also reduces sunitinib-induced cardiotoxicity in mice ( Yang et al, 2019b ). However, autophagy is a double-edged sword in myocardial tissue depending on the type and duration of stress.…”

Preventive effect of trimetazidine on contrast-induced nephropathy undergoing percutaneous coronary intervention in elderly moderate and high risk diabetics stratified by mehran score

“…Rate and increase in the efficiency of utilizing oxygen during myocardial hypoxia; (b) reduce intracellular acidosis and inorganic phosphorus accumulation during cardiac ischemia; (c) reduce intracellular sodium and calcium accumulation, and reduce The cell damage caused by it protects mitochondrial function and energy metabolism; (d) inhibits the accumulation of white blood cells to the ischemic site and reduces tissue damage. 19–22 TMZ protects cardiomyocytes from ischemia and hypoxia through these pathways, and achieves anti ischemia effect at the cellular level. TMZ has been shown to have strong antioxidant effect in myocardium, kidney, and liver of rats with ischemia-reperfusion injury.…”