Melatonin alleviates postinfarction cardiac remodeling and dysfunction by inhibiting Mst1

Abstract

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.

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

“…Accumulating studies indicate that melatonin have protective effects against DCM . Our previous study demonstrated that melatonin alleviated left ventricular remodeling and cardiac dysfunction after myocardial infarction . The mechanisms were associated with enhanced cardiomyocyte autophagy and reduced cardiomyocyte apoptosis.…”

“…Melatonin was initially dissolved in absolute ethanol and then diluted in sterile water to a final concentration of 0.5% ethanol. After constructing the DM model, mice were daily orally gavaged with melatonin (20 mg/kg/day) for 4 weeks …”

“…Total proteins were then separated by SDS‐PAGE, blotted, and probed with antibodies. The blots were scanned and quantified by densitometry analysis using an image analyzer Quantity One System (Bio‐Rad, Richmond, CA, USA) as previously described …”

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

“…After homogenizing and centrifuging at 12 000  g for 15 minutes at 4°C, the supernatant was mixed with the working reagent and then assessed by a microplate luminescence luminometer. As before, the contents of ROS were assessed by electron paramagnetic resonance spectroscopy according to Mellin's methods 41. Data were representative of three biological repeats.…”

Dietary Sources and Bioactivities of Melatonin

“…Besides, melatonin was closely related with reverse remodeling after cardiac resynchronization therapy in patients with heart failure and ventricular dyssynchrony [260]. Furthermore, it was observed that melatonin could markedly improve cardiac dysfunction, mitigate cardiac remodeling after myocardial infarction, increase the level of autophagy, attenuate apoptosis, regulate the integrity and restore the function of mitochondria through the inhibition of mammalian Ste20-like kinase 1 (Mst1) and the promotion of SIRT1, indicating the Mst1/SIRT1 signaling was involved [261]. …”