Pre-Treatment with Melatonin Enhances Therapeutic Efficacy of Cardiac Progenitor Cells for Myocardial Infarction

Abstract

Background/Aims: Melatonin possesses many biological activities such as antioxidant and anti-aging. Cardiac progenitor cells (CPCs) have emerged as a promising therapeutic strategy for myocardial infarction (MI). However, the low survival of transplanted CPCs in infarcted myocardium limits the successful use in treating MI. In the present study, we aimed to investigate if melatonin protects against oxidative stress-induced CPCs damage and enhances its therapeutic efficacy for MI. Methods: TUNEL assay and EdU assay were used to detect the effects of melatonin and miR-98 on H₂O₂-induced apoptosis and proliferation. MI model was used to evaluate the potential cardioprotective effects of melatonin and miR-98. Results: Melatonin attenuated H₂O₂-induced the proliferation reduction and apoptosis of c-kit⁺ CPCs in vitro, and CPCs which pretreated with melatonin significantly improved the functions of post-infarct hearts compared with CPCs alone in vivo. Melatonin was capable to inhibit the increase of miR-98 level by H₂O₂ in CPCs. The proliferation reduction and apoptosis of CPCs induced by H₂O₂ was aggravated by miR-98. In vivo, transplantation of CPCs with miR-98 silencing caused the more significant improvement of cardiac functions in MI than CPCs. MiR-98 targets at the signal transducer and activator of the transcription 3 (STAT3), and thus aggravated H₂O₂-induced the reduction of Bcl-2 protein. Conclusions: Pre-treatment with melatonin protects c-kit+ CPCs against oxidative stress-induced damage via downregulation of miR-98 and thereby increasing STAT3, representing a potentially new strategy to improve CPC-based therapy for MI.

Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in pulmonary hypertensive newborn sheep

“…Similarly, maternal melatonin regulates fetal organogenesis and functions, such as adrenal gland, that are critical for the successful adaptation of the neonate to extra-uterine environment [83]. Furthermore, some studies show that both light/dark environmental cues [84] or melatonin treatment [85] turns on/off microRNA programs that control the REDOX state of cells after many complete proliferative cycles, favoring a longlasting cardioprotective state. In addition, melatonin treatment affects oocytes DNA methylation pattern, reversing the effects of oocyte aging [86].…”

Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

“…The same was observed in cardiomyopathy induced by streptozotocin (103) or doxorubicin (104). In a murine model of myocardial infarction treated with cardiac progenitor cells, exposure of cells to melatonin enhances therapeutic efficacy of cardiac progenitor cells for myocardial infarction (105). Collectively, the results of Tables 1 and 2 indicate that the administration of melatonin effectively counteracts some of the disrupting effects seen in diet-induced obesity in animals insulin resistance, dyslipidemia and obesity, and the consequences of ischemic and non-ischemic heart disease.…”

Long non-coding RNAs and microRNAs as crucial regulators in cardio-oncology

“…In contrast to these observations, miR-98 upregulation in cardiac progenitor cells following hydrogen peroxide treatment has been reported to lead to increased apoptosis. Inhibition of miR-98 was found to be protective against cardiac progenitor cell injury through regulation of STAT3 [ 297 ]. The confounding patterns of miR-98 expression regarding having either protective or detrimental roles in the context of cardiovascular function might be owed to its participation in a conserved stress response.…”