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.
Highlights
Chronic heart failure (CHF), which attacks over 26 million people worldwide, remains to be a major cause of mobility and mortality for the elderly people (Savarese and Lund, 2017)
Mice developed maladaptive cardiac hypertrophy, represented by a significant increase in left ventricular internal end-diastolic dimensions (LVIDd, sham + PBS vs transverse aortic constriction (TAC) + PBS, p < 0.001, Figure 1A,B; Supplementary Table S3) and impairment of cardiac ejection function (EF, sham + PBS vs TAC + PBS, p 0.002, Figure 1C; Supplementary Table S3) 4 weeks after TAC compared to sham control, which were notably blunted by the treatment of trimetazidine
TAC mice exhibited a significant increase in left ventricular weight (Figure 1F), and cross-sectional area (CSA) of cardiomyocytes (CSA, sham + PBS vs TAC + PBS, p < 0.0001, Figure 1D,E), whereas trimetazidine-treated TAC mice showed relieved hypertrophy in these direct measurements vs PBS-treated TAC mice (Figure 1D,F)
Summary
Chronic heart failure (CHF), which attacks over 26 million people worldwide, remains to be a major cause of mobility and mortality for the elderly people (Savarese and Lund, 2017). Hypertension, characterized by the left ventricular (LV) pressure overload and the accompanied neuroendocrine disorders, induces cardiac hypertrophy and arrhythmias, eventually leads to heart failure (Zhou et al, 2017; Forrester et al, 2018). Increasing evidences suggested that the cardiac metabolic abnormalities and the resultant myocardial starvation and dysfunction were the common pathway leading to heart failure (Knowlton et al, 2014; Riehle and Abel, 2016). Glucose replaced the FFA to function as the main substrates for energy generation in pathological states (Fukushima et al, 2015), which even occurred in the very early stage of pressure overload-induced heart failure (Zhang et al, 2013). To relieve the myocardial insulin resistance raised as a promising novel approach for the treatment of heart failure (Neubauer, 2007; Knowlton et al, 2014; Fukushima et al, 2015)
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