ABSTRACT
Melatonin is a hormone produced by the pineal gland, and it has extensive beneficial effects on various tissue and organs; however, whether melatonin has any effect on cardiac fibrosis in the pathogenesis of diabetic cardiomyopathy (DCM) is still unknown. Herein, we found that melatonin administration significantly ameliorated cardiac dysfunction and reduced collagen production by inhibiting TGF-ß1/Smads signaling and NLRP3 inflammasome activation, as manifested by downregulating the expression of TGF-ß1, p-Smad2, p-Smad3, NLRP3, ASC, cleaved caspase-1, mature IL-1ß, and IL-18 in the heart of melatonin-treated mice with diabetes mellitus (DM). Similar beneficial effects of melatonin were consistently observed in high glucose (HG)-treated cardiac fibroblasts (CFs). Moreover, we also found that lncRNA MALAT1 (lncR-MALAT1) was increased along with concomitant decrease in microRNA-141 (miR-141) in DM mice and HG-treated CFs. Furthermore, we established NLRP3 and TGF-ß1 as target genes of miR-141 and lncR-MALAT1 as an endogenous sponge or ceRNA to limit the functional availability of miR-141. Finally, we observed that knockdown of miR-141 abrogated anti-fibrosis action of melatonin in HG-treated CFs. Our findings indicate that melatonin produces an antifibrotic effect via inhibiting lncR-MALAT1/miR-141-mediated NLRP3 inflammasome activation and TGF-ß1/Smads signaling, and it might be considered a potential agent for the treatment of DCM.
Subject(s)
Diabetes Mellitus, Experimental/complications , Diabetic Cardiomyopathies/pathology , Fibrosis/drug therapy , Gene Expression Regulation/drug effects , Heart Diseases/drug therapy , Melatonin/pharmacology , Animals , Antioxidants/pharmacology , Diabetic Cardiomyopathies/epidemiology , Fibrosis/etiology , Fibrosis/metabolism , Fibrosis/pathology , Heart Diseases/etiology , Heart Diseases/metabolism , Heart Diseases/pathology , Inflammasomes/antagonists & inhibitors , Inflammasomes/genetics , Inflammasomes/metabolism , Male , Mice , MicroRNAs/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , RNA, Long Noncoding/genetics , Smad Proteins/antagonists & inhibitors , Smad Proteins/genetics , Smad Proteins/metabolism , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
Coriolus versicolor (CV) is a traditional medicine and food mushroom. Our previous study demonstrated that CV extract exhibited anti-hyperglycemia and anti-insulin resistance effects. However, the effect of CV on cardiac function in diabetic cardiomyopathy (DCM) remains unclear. Therefore, we aimed to investigate the effect of CV on cardiac function in diabetes mellitus (DM) rats. We found that the cardiac dysfunction of DM rats was markedly improved by CV extract treatment. CV extract administration significantly attenuated cardiac fibrosis in DM rats, which was accompanied by suppressed transforming growth factor beta 1 (TGF-ß1)/Smad signaling as indicated by decreased levels of TGF-ß1, p-Smad2, and p-Smad3 and increased Smad7 expression. Moreover, CV extract treatment significantly alleviated cardiac inflammation as shown by decreased levels of NLRP3 receptor, cleaved caspase-1, IL-1ß, and IL-18 in DM rats at least partly due to the inhibition of the NF-κB. In addition, high-glucose treatment induced cardiac fibrosis and increased cardiac inflammation in cardiac fibroblast cells, but these effects were ameliorated by CV extract treatment. Therefore, we conclude that the protective effect of CV on DCM is associated with the suppression of TGF-ß1/Smad signaling and attenuation of NLRP3 inflammasome activation, suggesting that CV extract may be a potential therapeutic agent for DCM.
