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Objective: To determine the effect of trimetazidine on cardiac function and exercise tolerance in primary hypertension patients with type 2 diabetic., Methods: In this randomized, double-blind, placebo-controlled prospective study, 60 primary hypertensive patients with diabetic were equally assigned into two groups, patients received trimetazidine (20 mg, 3 times a day) or placebo for 1 year. Echocardiography, cardiopulmonary exercise testing were performed; and the plasma N terminal pro B type natriuretic peptide (NT-ProBNP), hr-CRP, TNF-α, angiotensin Ⅱ and endothelin concentration were determined before and after treatment., Results: In trimetazidine group, the left ventricular mass index, the mitral flow velocity E wave to A wave ratio (E/A), the peak early diastolic velocity (V E ) to late diastolic velocity (V A ) ratio (V E /V A ) and the peak systolic velocity (Vs) were significantly improved, the plasma NT-ProBNP level was significantly decreased, and the exercise time, metabolic equivalent, maximal oxygen uptake and anaerobic threshold were significantly increased (all P <0.05); plasma concentration of hr-CRP, TNF-α, angiotensin Ⅱ and endothelin were significantly reduced after trimetazidine treatment, compared with baseline (all P <0.05) and with placebo (all P <0.05). There were no significant differences in any of above parameters after treatment in placebo group (all P >0.05). No severe adverse reaction was observed in both groups., Conclusions: For patients with both hypertension and diabetes, trimetazidine can improve cardiac function and increase exercise tolerance.

Objective To explore the effects of trimetazidine (TMZ) on the foam cell formation and its underlying mechanism in oxidized low-density lipoprotein (ox-LDL)-induced macrophages. Methods RAW264.7 cells were stimulated with ox-LDL to establish a foam cell model derived from macrophages. In the experiment, the foam cells were divided into control group (medium), model group (ox-LDL 60 μg/mL), chloroquine (CQ) group (ox-LDL 60 μg/mL combined with CQ 10 mmol/L) and TMZ group (ox-LDL 60 μg/mL combined with TMZ 80 μmol/L, CQ 10 mmol/L). The formation of foam cells was measured by oil red O staining. The levels of total cholesterol (TC) and free cholesterol (FC) in the foam cells were detected using ELISA. Autophagy was observed using MDC staining. Picogreen staining and quantitative fluorescence were performed to detect the formation of macrophage extracellular traps (MET). Then, the mRNA expression of LC3B, P62, inflammasome (NLRP3, ASC, caspase-1) and cholesterol efflux-related genes (ABCA1, ABCG1) were examined by real-time quantitative PCR. Results Compared with the model group, the expression of LC3B mRNA increased significantly, and P62 expression decreased in TMZ combined with CQ group. Meanwhile, the levels of TC, FC, CE/TC, and the expression of NLRP3, ASC, caspase-1 in TMZ combined with CQ group were reduced obviously. Furthermore, the formation of MET in TMZ combined with CQ group was promoted. However, the CQ group showed the opposite results. Conclusion Trimetazidine promotes cholesterol efflux in foam cells via activating autophagy and increasing the formation of MET, as well as inhibiting NLRP3 inflammasome.

Objective: 5-Hydroxytrytamine (5-HT) system was reported to be associated with myocardial infarction (MI) and depression. The aim of the present study was to study the effect of trimetazidine on 5-HT in MI and/or depression rats. Methods: Ninety rats were divided into three groups: trimetazidine, sertraline and saline groups ( n= 30 in each group), and pretreated with trimetazidine, sertarline, or saline, respectively, by gavage once a day for 4 weeks. Thereafter, each group was further divided into three subgroups: MI subgroup, depression subgroup, and MI+ depression subgroup. Serum 5-HT, platelet 5-HT, 5-HT(2A) receptor (5-HT(2A)R), and serotonin transporter (SERT) were detected by enzyme linked immunosorbent assay. Results: Similar to sertarline, comparing to saline, trimetazidine treatment increased serum 5-HT [(221±23) pg/ml vs. (176±11) pg/ml; (395±31) pg/ml vs. (195±5) pg/ml; (348±28) pg/ml vs. (183±10) pg/ml], platelet 5-HT [(305±22) pg/ml vs. (130±27) pg/ml; (252±18) pg/ml vs. (175±5) pg/ml; (241±26) pg/ml vs. (181±11) pg/ml], and platelet 5-HT(2A)R levels [(247±13) pg/ml vs. (197±12) pg/ml; (320±13) pg/ml vs. (193±18)pg/ml; (334±17) pg/ml vs. (206±15) pg/ml]), and lowered platelet SERT levels [(248±11) pg/ml vs. (323±36) pg/ml; (188±7) pg/ml vs. (278±20) pg/ml; (170±23) pg/ml vs. (282±22) pg/ml] in MI, depression and MI+ depression subgroups, respectively (all P< 0.05). When compared the effect of trimetazidine and sertarline treatment, serum 5-HT and platelet 5-HT(2A)R in MI group were significantly lower in trimetazidine than in sertraline group ( P< 0.05), while serum 5-HT and platelet 5-HT, 5-HT(2A)R in depression group rats were significantly higher in trimetazidine than in sertraline group ( P< 0.05).Interestingly, platelet 5-HT(2A)R in MI+ depression rats was much higher in trimetazidine than in sertraline group ( P< 0.05). Conclusions: Trimetazidine, a kind of myocardial metabolism agent, could play a role on the regulation of 5-HT, 5-HT(2A)R, and SERT levels in rats with MI and/or depression.

Objectives: To investigate the effects of trimetazidine (TMZ) on the oxidative stress injury in adipose-derived mesenchymal stem cells (ADSCs)., Methods: ADSCs derived from adipose tissue of SD rats were characterized by flow cytometry and multiline age differentiation. ADSCs apoptosis was induced by H2O2 in vitro , Dirrerent concentration of TMZ (250 μmol/L, 500 μmol/L) was used to protect ADSCs from apoptosis. The morphological features of apoptotic ADSCs were analyzed by Hoechst 33342, mitochondrial potential and structure was analyzed by JC-1 staining and electron microscope, respectively. The apoptotic proteins were detected by Western blot. The effect of TMZ on antioxidant capacity of ADSCs was evaluated by detecting reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA)., Results: The isolated ADSCs expressed high levels of CD29 and CD90, low levels of CD34 and CD45 and no expression of CD31. ADSCs could be induced to adipocyte and osteoplastic cells. After being treated by H2O2, ADSCs displayed apoptosis characteristics with increased number of apoptotic cells, decreased mitochondrial transmembrane potential and damaged mitochondria. The expressions of apoptotic proteins, including Bax, Bad, and Caspase3, were dramatically increased compared to the controls; however, the anti-apoptotic protein Bcl2 was decreased. At the meantime, the contents of ROS and MDA were elevated, but the concentrations of SOD and GSH were reduced. The treatment of TMZ could partly reverse above negative impacts to ADSCs., Conclusion: TMZ could improve the survival rate of ADSCs by enhancing anti-oxidant defense systems to remove excessive ROS and regulating the expression of protective protein.

Objective: To explore the effect of trimetazidine pre-treatments on serum 5-hydroxytryptamine (5-HT) and serotonin transporter (SERT), platelet 5-HT and SERT in the Sprague Dawley rats with myocardial infarction(MI), depression, and myocardial infarction co-exist with depression (MI+ depression) and in sham operated rats. Methods: Eighty rats were divided into treatment group and placebo (saline) group by the random number table method ( n =40 each group). After 4 weeks' treatment with trimetazidine, or saline, these rats were assigned to respective sham subgroup, depression subgroup, MI subgroup, MI + depression subgroup ( n =10 each subgroup). All rats were sacrificed 3 days later. 5-HT in serum and platelet, and SERT in serum and platelet of the rats were tested by enzyme linked immunosorbent assay (ELISA). Data were analyzed by SPSS 17.0. Results: In saline group, serum and platelet 5-HT levels were significantly lower in MI, depression and MI+ depression subgroup compared to sham subgroup (all P <0.01). In trimetazidine pre-treatment group, serum and platelet 5-HT levels were significantly higher in the depression subgroup, MI subgroup, MI + depression subgroup than respective subgroups of saline pretreated rats (all P <0.01). In saline group, SERT in serum and platelet were higher in MI, depression, MI+ depression subgroup than the sham subgroup and statistical significance was found between MI+ depression subgroup and sham subgroups. Serum SERT level was significantly lower in the treatment group compared to saline group for sham rats ( P <0.01). In treatment group, serum SERT level was higher in MI, depression and MI+ depression subgroups compared to respective subgroup treated with saline while the statistical significance was found in depression subgroup between trimetazidine pre-treatment and saline control groups. Platelet SERT was higher in MI, depression and MI+ depression subgroups compared to sham subgroup post saline treatment. Platelet SERT was significantly lower in MI, depression and MI+ depression subgroups post trimetazidine pre-treatment than in respective subgroups post saline treatment (all P <0.01). Conclusions: Our study results indicate that trimetazidine pretreatment could increase the levels of 5-HT and SERT in serum and 5-HT in platelet, and decrease the level of SERT in platelet in the rat MI and depression model.

Objective: The aim of study is to investigate the changes of structure and function of heart in diabetic rat after myocardial infarction, and to study the expression of the GLUT4 and the effects of trimetazidine on the ventricular remodeling., Methods: Type 2 diabetes rat was made by feeding with a diet enriched with sucrose, fat and cholesterol for six weeks and then injecting streptozocin intraperitoneally, then the myocardial infarction by ligating coronary artery. The living rats were randomly divided into three groups twenty-four hours after operation: placebo; trimetazidine and sham operated with diabetes. And other rats which was fed with normal diet were divided into myocardial infarction group without diabetes and sham operated group without diabete. The treat group was intragastric administrated with trimetazidine which was solved in distilled water (30 mgxkg(-1) 1xd(-1)), and others were poured with parts aequalis distilled water. After six weeks, echocardiographic and hemodynamic studies were performed, ventricular were weighed, myocardial infarct size and myocardial collagen volume fraction (CVF) of non-infarction area were detected also. GLUT4 mRNA in the myocardium away from infarction region were measured with fluorescent quantitation RT-PCR and GLUT4 protein were measured with Western blot., Results: Six weeks after diabetes complicating with myocardial infarction, comparing with sham operated group without diabete, diabetes sham operated group and myocardial infarction group without diabete, LVDd of diabetes complicating with myocardial infarction group was increased significantly; the systolic and diastolic function with left ventricular were decreased significantly, VWI and CVF were increased significantly; comparing with placebo group, diastolic function of left ventricular in trimetazidine group was improved significantly (4.7 +/- 1.7 vs 6.8 +/- 1.6, P < 0.05); CVF (3.9 +/- 0.2)% vs (6.3 +/- 0.4)%, (P < 0.05) was decreased significantly, but LVDd, VWI and the systolic function was not chang significantly. The expression of GLUT4 mRNA and protein in sham operated with diabetes and diabetic with myocardial infarction descended significantly compared with sham operated group without diabete (P < 0.01). And in trimetazidine group, GLUT4 protein moderately increased (P < 0.05) compared with placebo group., Conclusion: Trimetazidine could improve the diastolic function of left ventricular. The expression of GLUT4 mRNA and protein in type 2 diabetes complicating with myocardial infarction decreased. Trimetazidine could improve the expression of GLUT4 mRNA and protein in diabetes complicating with myocardial infarction and inhibited myocardial fibrosis.

Objective: Aim of the present study was to investigate the effect of chronic trimetazidine treatment on atrial energy metabolism and endothelial function in a canine model of chronic atrial fibrillation (AF)., Methods: Eighteen canines were randomly divided into sham-operated group (n = 6), atrial pacing group (n = 6), and trimetazidine group (n = 6). In atrial pacing group and trimetazidine group, dogs were atrial paced at 400 beats per minutes for 6 weeks. Trimetazidine at 5 mgxkg(-1)xd(-1) was given one day before rapid atrial pacing for 6 weeks. Creatine phosphate (CrP), adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in atrial tissue were analyzed by high-performance liquid chromatography. Total adenosine (TAN) was calculated. The expression of endothelial nitric oxide synthase (eNOS) in atrial tissue was determined by Western blot and immunohistochemical staining. In addition, plasma levels of von Willebrand factor (vWF) was quantified with enzyme-linked immunoadsorbent assay and NO(2)(-)/NO(3)(-) (NOx) was determined by nitrate reductase method., Results: Atrial CrP (P < 0.01) and CrP/ATP were significantly decreased in paced atrium compared to atrium from sham-operated group (P < 0.05) while ATP, ADP, AMP and TAN remained unchanged (all P > 0.05). Plasma vWF was significantly increased and plasma NOx significantly decreased in paced animals compared to sham-operated animals. Atrial expression of eNOS was also significantly reduced in paced animals (P < 0.01). Trimetazidine treatment did not alter the contents of CrP, ATP, ADP, AMP and TAN, but significantly increased atrial eNOS expression (P < 0.05), decreased plasma vWF (P < 0.01) and increased plasma NOx concentration., Conclusion: Trimetazidine treatment affect chronic AF induced disturbance in energy metabolism but may improve endothelial function through a NOx depended manner.

Objective: To investigate the protective effects of trimetazidine on rabbit myocardium in ischemia and reperfusion., Methods: Fourty rabbits were divided into five groups randomly: normal control group, ischemia control group, ischemia and drug intervention group, reperfusion control group, reperfusion and drug intervention group. Ischemia lasted for 30 minutes and reperfusion was given for 30 minutes. Serum CPK, SOD activities and MDA concentrations were measured in each group and ischemia tissue ATP concentrations were also measured. Heart tissue was examined with electron microscope in each group., Results: (1) Serum concentrations of MDA in ischemia and drug intervention group were significantly different from those in ischemia control group [(4.09+/-0.40 vs 4.79+/-0.92)nmol/ml, P<0.01], serum activities of CPK [(1322+/-1148 vs 1498+/-190) NU/ml], SOD[(324+/-71 vs 288+/-54)NU/ml] were not significantly different between ischemia and drug intervene group and ischemic control group (PP>0.05,respectively). (2) Serum activities of CPK [(1512+/-226 vs 1904+/-203) NU/ml], SOD[(213+/-71 vs 119+/-55) NU/ml], concentrations of MDA [(6.09+/-0.69 vs 7.43+/-0.20)nmol/ml] and concentrations of ATP[(1.401+/-0.248 vs 0.629+/-0.175) micromol/g] in ischemia heart tissue of reperfusion and drug intervention group were significantly different from those in reperfusion control group (P<0.001 - 0.01 respectively). (3) There were significant differences in electron microscopic observation between intervention group and control group., Conclusion: Trimetazidine can improve cardiac mitochondrial metabolism and scavenge oxygen free radicals. Trimetazidine has cardioprotective function during ischemia and reperfusion.