This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1 ) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1 mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3-II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.

AimsTo evaluate the safety profile and efficacy of bone marrow mononuclear cells (BMMNC) transplantation for ST-segment elevation myocardial infarction (STEMI) by assessing patients and their left ventricular function at up to 4 years follow-up.Methods and resultsEighty-six patients with STEMI who had successfully undergone percutaneous coronary intervention (PCI) were randomized to receive intracoronary injection of BMMNC (n = 41) or saline (n = 45). Left ventricular ejection fraction, as evaluated by UCG, was markedly improved at 6 months (0.484 ± 0.5 vs. 0.457 ± 0.6, P = 0.001), 1 year (0.482 ± 0.7 vs. 0.446 ± 0.6, P < 0.001), and 4 years (0.505 ± 0.8 vs. 0.464 ± 0.8, P < 0.001) after BMMNC transplant when compared with control group. However, the current cell therapy did not improve the myocardial viability of the infarcted area as assessed by single-photon emission computed tomography analysis at 4 years post-transplant (0.263 ± 0.007 in BMMNC group vs. 0.281 ± 0.008 in control group, P = 0.10). During the follow-up period, one control group case (2.2%) of in-stent restenosis was confirmed by coronary angiography and underwent repeat PCI. Also during follow-up, one death (2.2%) occurred in the control group, and one patient (2.4%) in the BMMNC group had transient acute heart failure.ConclusionThis study indicates that intracoronary delivery of autologous BMMNC is safe and feasible for STEMI patients who have undergone PCI, and can lead to long-term improvement in myocardial function.

Melatonin reportedly protects against several cardiovascular diseases including ischemia/reperfusion (I/R), atherosclerosis, and hypertension. The present study investigated the effects and mechanisms of melatonin on cardiomyocyte autophagy, apoptosis, and mitochondrial injury in the context of myocardial infarction (MI). We demonstrated that melatonin significantly alleviated cardiac dysfunction after MI. Four weeks after MI, echocardiography and Masson staining indicated that melatonin notably mitigated adverse left ventricle remodeling. The mechanism may be associated with increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin significantly inhibited Mst1 phosphorylation while promoting Sirt1 expression after MI, which indicates that Mst1/Sirt1 signaling may serve as the downstream target of melatonin. We thus constructed a MI model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1 ) mice. The absence of Mst1 abolished the favorable effects of melatonin on cardiac injury after MI. Consistently, melatonin administration did not further increase autophagy, decrease apoptosis, or alleviate mitochondrial integrity and biogenesis in Mst1 knockout mice subjected to MI injury. These results suggest that melatonin alleviates postinfarction cardiac remodeling and dysfunction by upregulating autophagy, decreasing apoptosis, and modulating mitochondrial integrity and biogenesis. The attributed mechanism involved, at least in part, Mst1/Sirt1 signaling.