Influence of trimetazidine on myocardial injury in mice with diabetic cardiomyopathy.

INTRODUCTION: The prevalence of diabetes mellitus is increasing year by year globally, and diabetic cardiomyopathy (DCM), as the most common complication of type 2 diabetes mellitus, seriously affects the prognosis of patients. Trimetazidine (TMZ), as a drug affecting myocardial energy metabolism, mainly reduces the oxidation rate of ß-oxidation by inhibiting 3-ketoacyl-CoA thiolase (3-KAT), a key enzyme in ß-oxidation of free fatty acid (FFA), so that the energy metabolism substrate of cardiomyocytes preferentially selects glucose rather than fatty acids, increases the content of intracellular adenosine triphosphate (ATP), enhances the contractile function of cardiomyocytes, and improves the state of cellular ischemia and hypoxia. Previous studies have shown that TMZ is closely related to the activation and induction of apoptosis of the MAPK pathway and AMPK pathway, and plays a role in the treatment of diabetic cardiomyopathy, but the specific mechanism is still unclear. OBJECTIVE: This study aims to investigate the impact of TMZ on myocardial damage in mice exhibiting diabetic cardiomyopathy (DCM), and to furnish a laboratory foundation for the clinical treatment of diabetic cardiomyopathy. METHOD: Male db/db mice (6 weeks old, n = 21) and male wild-type (wt) (6 weeks old, n = 20) mice were selected for the study. The wt mice were randomly assigned to the wt group (n = 10) and wt + TMZ group (n = 10), while the remaining db/db mice were randomly allocated to the db/db group (n = 11) and db/db + TMZ group (n = 10). Following 8 weeks of feeding, the wt + TMZ group and db/db + TMZ group received TMZ via gavage, whereas the remaining groups were administered physiological saline. Periodic measurements of blood glucose, blood lipids, and myocardial enzymes were conducted in mice, with samples obtained after the 12th week for subsequent biochemical analysis, myocardial pathology assessment, immunohistochemistry, western blot analysis, and TUNEL staining (TdT-mediated dUTP Nick-End Labeling). RESULT: GLU, TC, TG, LDL-C, and CK-MB levels were significantly higher in db/db mice compared to wt mice (GLU: M ± SD wt 5.94 ± 0.37, db/db 17.63 ± 0.89, p < 0.05, ES = 0.991; TC: M ± SD wt 3.01 ± 0.32, db/db 6.97 ± 0.36, p < 0.05, ES = 0.972; TG: M ± SD wt 0.58 ± 0.2, db/db 1.75 ± 0.14, p < 0.05, ES = 0.920; LDL-C: M ± SD wt 1.59 ± 0.12, db/db 3.87 ± 0.14, p < 0.05, ES = 0.989; CK-MB: M ± SD wt 0.12 ± 0.01, db/db 0.31 ± 0.04, p < 0.05, ES = 0.928). HDL-C levels were significantly lower in db/db mice (M ± SD wt 1.89 ± 0.08, db/db 0.64 ± 0.09, p < 0.05, ES = 0.963). Histopathological analysis confirmed myocardial damage in db/db mice. Treatment with TMZ reduced GLU, TC, TG, LDL-C, and CK-MB levels (p < 0.05, ES > 0.9) and increased HDL-C levels compared to untreated db/db mice. Additionally, TMZ treatment significantly decreased myocardial cell apoptosis (p < 0.05, ES = 0.980). These results demonstrate the efficacy of TMZ in reversing myocardial injury in DCM mice. CONCLUSION: TMZ can mitigate myocardial damage in db/db mice by downregulating the expression of caspase-12, a protein associated with the endoplasmic reticulum stress (ERS) cell apoptosis pathway, consequently diminishing cell apoptosis. This underscores the protective efficacy of TMZ against myocardial damage in mice afflicted with DCM.

Prognostic Utility of Monocyte to High-Density Lipoprotein Ratio in Patients With Acute Coronary Syndrome: A Meta-Analysis.

BACKGROUND: The monocyte to high-density lipoprotein ratio (MHR) has been used to predict adverse clinical outcomes in patients with acute coronary syndrome (ACS). This meta-analysis aimed to evaluate the prognostic utility of MHR in patients with ACS. MATERIALS AND METHODS: We comprehensively searched for relevant studies in Pubmed, Embase, CNKI, WanFang and VIP databases until March 12, 2019. Epidemiologic studies investigating the association between MHR and major adverse cardiovascular events (MACE) or all-cause mortality in patients with ACS were included. Pooled effect was expressed as risk ratios (RR) with 95% confidence intervals (CI) for the highest versus the reference lower MHR group. RESULTS: Eight studies involving 6,480 patients with ACS were included and analyzed. Meta-analysis indicated that the highest MHR was significantly associated with higher risk of MACE (RR 1.65; 95%CI 1.36-2.02) and all-cause mortality (RR 2.61; 95%CI 1.29-4.89) after adjusting for the conventional confounders. The prognostic values of MACE with the highest MHR caused no significant changes in the in-hospital follow-up (RR 1.76; 95%CI 1.34-2.32) and >6 months follow-up (RR 1.68; 95%CI 1.08-2.62) subgroups. Furthermore, ST elevation myocardial infarction patients with the highest MHR had a 2.07-fold higher risk of in-hospital MACE (RR 2.07; 95%CI 1.52-2.80). CONCLUSIONS: Elevated MHR is independently associated with an increased risk of MACE and all-cause mortality in patients with ACS. MHR may serve as a potential prognostic indicator for ACS prognosis.

Salidroside attenuates oxidized low­density lipoprotein­induced endothelial cell injury via promotion of the AMPK/SIRT1 pathway.

Oxidized low­density lipoprotein (ox­LDL)­induced endothelial damage contributes to the initiation and pathogenesis of atherosclerosis. Salidroside can alleviate atherosclerosis and attenuate endothelial cell injury induced by ox­LDL. However, the mechanisms involved in this process are not fully understood. Therefore, the purpose of the present study was to investigate the role of the adenosine monophosphate­activated protein kinase (AMPK)/sirtuin (SIRT)1 pathway in the protection of salidroside against ox­LDL­induced human umbilical vein endothelial cells (HUVECs) injuries. The results revealed that salidroside reverses ox­LDL­induced HUVECs injury as demonstrated by the upregulation of cell viability and downregulation of LDH release. In addition, salidroside increased the expression of the SIRT1 protein in ox­LDL­treated HUVECs. Next, it was demonstrated that SIRT1 knockdown induced by transfection with small interfering (si)RNA targeting SIRT1 (siSRT1) abolished the protection of salidroside against ox­LDL­induced HUVECs injuries. This was illustrated by a decrease in cell viability and an increase in LDH release, caspase­3 activity and apoptosis rate. Furthermore, salidroside mitigated ox­LDL­induced reactive oxygen species production, upregulated malondialdehyde content and NADPH oxidase 2 expression and decreased superoxide dismutase and glutathione peroxidase activities, while these effects were also reversed by siSIRT1 transfection. In addition, it was demonstrated that salidroside suppressed ox­LDL­induced mitochondrial dysfunction as demonstrated by the increase in mitochondrial membrane potential and decreases in cytochrome c expression, and Bax/Bcl­2 reductions. However, these effects were eliminated by SIRT1 knockdown. Finally, it was demonstrated that salidroside significantly upregulated the phosphorylated­AMPK expression in ox­LDL­treated HUVECs and AMPK knockdown induced by transfection with AMPK siRNA (siAMPK) leads to elimination of the salidroside­induced increase in cell viability and the decrease in LDH release. Notably, siAMPK transfection further decreased the expression of SIRT1. In conclusion, these results suggested that salidroside protects HUVECs against ox­LDL injury through inhibiting oxidative stress and improving mitochondrial dysfunction, which were dependent on activating the AMPK/SIRT1 pathway.