Melatonin therapy for diabetic cardiomyopathy: A mechanism involving Syk-mitochondrial complex I-SERCA pathway.

Abstract

Melatonin and its metabolites have been demonstrated to modulate the glucose, dyslipidemia and other metabolic disorders. This study aimed to explore a novel mechanism responsible for diabetic cardiomyopathy development, and also validated whether melatonin played a protective role in repairing damaged heart in the diabetes setting. Our data demonstrated that spleen tyrosine kinase (Syk) was activated by chronic high-glucose stimulus and contributed to the development of diabetic cardiomyopathy. However, genetic ablation of Syk or supplementation of melatonin to inhibit Syk activation improved diabetic myocardial function, reduced cardiac fibrosis and preserved cardiomyocytes viability. Mechanistically, activated Syk repressed the expression and activity of mitochondrial complex I (COX-1), unfortunately evoking mitochondrial and/or cellular ROS overproduction. Subsequently, excessive superoxide facilitated SERCA peroxidation which failed to re-uptake the cytoplasmic calcium back into endoplasmic reticulum (ER), leading to cellular calcium overload. Finally, activated oxidative stress and calcium overload collectively promoted the high-glucose-induced cardiomyocytes death via caspase-9-related mitochondrial apoptosis and caspase-12-involved ER apoptosis, respectively. Interestingly, inhibition of Syk via Syk genetic ablation or melatonin administration blocked Syk/COX-1/SERCA signalling pathways, and thus abolished mitochondrial- and ER-mediated cardiomyocyte death in the setting of diabetes. Based on these results, we suggest a novel pathway by which high-glucose stimulus induces diabetic cardiomyopathy is possibly through an activation of Syk/COX-1/SERCA axis which could be abrogated by melatonin treatment.

• Authors: Hao Zhou, Yan Yue, Jin Wang, Qiang Ma, Yundai Chen
• Journal: Cellular signalling (Cell Signal) Vol. 47 Pg. 88-100 (Jul 2018) ISSN: 1873-3913 [Electronic] England
• PMID: 29601906 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Reactive Oxygen Species
• Troponin T
• Syk Kinase
• Syk protein, mouse
• Caspase 9
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Electron Transport Complex I
• Glucose
• Melatonin
• Calcium

Topics

• Animals
• Apoptosis (drug effects)
• Calcium (metabolism)
• Caspase 9 (metabolism)
• Diabetes Mellitus, Experimental (chemically induced, metabolism, pathology)
• Diabetic Cardiomyopathies (drug therapy)
• Down-Regulation (drug effects)
• Electron Transport Complex I (metabolism)
• Glucose (pharmacology)
• Melatonin (pharmacology, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (cytology, metabolism)
• Reactive Oxygen Species (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (metabolism)
• Signal Transduction (drug effects)
• Syk Kinase (deficiency, genetics, metabolism)
• Troponin T (metabolism)