Trimetazidine attenuates pressure overload-induced early cardiac energy dysfunction via regulation of neuropeptide Y system in a rat model of abdominal aortic constriction

Abstract

Background: Metabolism remodeling has been recognized as an early event following cardiac pressure overload. However, its temporal association with ventricular hypertrophy has not been confirmed. Moreover, whether trimetazidine could favorably affect this process also needs to be determined. The aim of the study was to explore the temporal changes of myocardial metabolism remodeling following pressure-overload induced ventricular hypertrophy and the potential favorable effect of trimetazidine on myocardial metabolism remodeling.

Methods: A rat model of abdominal aortic constriction (AAC)-induced cardiac pressure overload was induced. These rats were grouped as the AAC (no treatment) or TMZ group according to whether oral trimetazidine (TMZ, 40 mg/kg/d, for 5 days) was administered. Changes in cardiac structures were sequentially evaluated via echocardiography. The myocardial ADP/ATP ratio was determined to reflect the metabolic status, and changes in serum neuropeptide Y systems were evaluated.

Results: Myocardial metabolic disorder was acutely induced as evidenced by an increased ADP/ATP ratio within 7 days of AAC before the morphological changes in the myocardium, accompanied by up-regulation of serum oxidative stress markers and expression of fetal genes related to hypertrophy. Moreover, the serum NPY and myocardial NPY-1R, 2R, and 5R levels were increased within the acute phase of AAC-induced cardiac pressure overload. Pretreatment with TMZ could partly attenuate myocardial energy metabolic homeostasis, decrease serum levels of oxidative stress markers, attenuate the induction of hypertrophy-related myocardial fetal genes, inhibit the up-regulation of serum NPY levels, and further increase the myocardial expression of NPY receptors.

Conclusions: Cardiac metabolic remodeling is an early change in the myocardium before the presence of typical morphological ventricular remodeling following cardiac pressure overload, and pretreatment with TMZ may at least partly reverse the acute metabolic disturbance, perhaps via regulation of the NPY system.

Keywords: Metabolic remodeling; Neuropeptide Y; Trimetazidine; Ventricular hypertrophy.

Fig. 1

Comparisons of the heart weight, left ventricular weight, and cell surface area of cardiomyocytes for rats from each group. a, Effects of AAC and TMZ pretreatment on HW/BW in rats from each group; b, effects of AAC and TMZ pretreatment on LVW/BW in rats from each group; c, effects of AAC and TMZ pretreatment on CSA of cardiomyocytes for rats from each group. AAC abdominal aortic constriction. TMZ trimetazidine, HW heart weight, BW body weight, LVW left ventricular weight, CSA cell surface area; n = 6 per group; 10 high magnification views with at least 100 cardiomyocytes in each view were analyzed to determine the CSA

Fig. 2

Comparisons of myocardial expression of fetal genes related to myocardial hypertrophy induced by AAC: results of real-time PCR analyses. a, Effects of AAC and TMZ pretreatment on mRNA levels of MHC-β in myocardium of rats from each group; b, effects of AAC and TMZ pretreatment on mRNA levels of ANF in myocardium of rats from each group. AAC abdominal aortic constriction, TMZ trimetazidine, ANF atrial natriuretic factor, MHC-β β myosin heavy chain; n = 4~6 per group, and samples were analyzed in triplicate. *, p < 0.05 compared with sham group at the same time point; #, p < 0.05 compared with AAC group at the same time point

Fig. 3

Comparison of ADP/ATP ratios in myocardium. AAC abdominal aortic constriction, TMZ trimetazidine; n = 4~6 per group and samples were analyzed in triplicate. *, p < 0.05 compared with sham group at the same time point; #, p < 0.05 compared with AAC group at the same time point

Fig. 4

Comparisons of serum activities of oxidative stress markers. a, Effects of AAC and TMZ pretreatment on MDA concentrations in rats from each group; b, effects of AAC and TMZ pretreatment on SOD activities in rats from each group. AAC abdominal aortic constriction, TMZ trimetazidine, MDA malonaldehyde, SOD superoxide dismutase; n = 4~6 per group and samples were analyzed in triplicate. *, p < 0.05 compared with sham group at the same time point; #, p < 0.05 compared with AAC group at the same time point

Fig. 5

Comparison of serum concentrations of NPY in rats from each group. AAC abdominal aortic constriction, TMZ trimetazidine, NPY neuropeptide Y; n = 4~6 per group and samples were analyzed in triplicate. *, p < 0.05 compared with sham group at the same time point; #, p < 0.05 compared with AAC group at the same time point

Fig. 6

Comparisons of mRNA levels of NPY-1R (a), NPY-2R (b), and NPY-5R (c) in the myocardium of rats from each group: results of real-time PCR analyses. TMZ trimetazidine, NPY neuropeptide Y; n = 4~6 per group and samples were analyzed in triplicate. *, p < 0.05 compared with sham group at the same time point; #, p < 0.05 compared with AAC group at the same time point

Fig. 7

Comparisons of protein levels of NPY-1R, NPY-2R, and NPY-5R in the myocardium of rats from each group at 2 days (a) and 7 days (b) after AAC: results of western blot analyses. TMZ trimetazidine, NPY neuropeptide Y, n = 4~6 per group and samples were analyzed in triplicate. *, p < 0.05 compared with sham group at the same time point; #, p < 0.05 compared with AAC group at the same time point