Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR‐141‐mediated NLRP3 inflammasome and TGF‐β1/Smads signaling in diabetic cardiomyopathy

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‐β1/Smads signaling and NLRP3 inflammasome activation, as manifested by downregulating the expression of TGF‐β1, p‐Smad2, p‐Smad3, NLRP3, ASC, cleaved caspase‐1, mature IL‐1β, 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‐β1 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‐β1/Smads signaling, and it might be considered a potential agent for the treatment of DCM.

Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease

“…In the field of cardiovascular effects, melatonin protects against ischemia/reperfusion injury (IRI) [ 62 , 117 , 118 , 119 , 120 , 121 ] and hypertension [ 122 , 123 , 124 ], as an endogenous effect, nutritional supplement, or acute parenteral administration [ 125 , 126 ]. In addition, it appears that other promising effects such as anti-apoptotic, anti-inflammatory [ 127 ], preconditioning [ 118 , 128 ], myocardial infarction [ 129 , 130 , 131 ], and even an implication in heart failure [ 132 , 133 , 134 , 135 ] have been documented. However, it seems than in some conditions, melatonin can have deleterious effects, as exaggerated collagen and glycosaminoglycans deposition and increased size in post-myocardial infarction scar have also been reported [ 136 , 137 ].…”

“…Some studies showed that melatonin produces a decrease in the myocardial scar, reduced fibrosis [ 134 ], and remodeling after myocardial infarction [ 130 ]. In the MARIA (Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty) study on reperfused STEMI patients, melatonin reduces infarct size 40% if administered in the first 2.5 h after symptom onset [ 125 , 129 ].…”

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

“…1 DM is associated with severe damage to multiple organ systems, such as the heart, eyes, and kidneys. [2][3][4] Recently, increasing attention has been paid to the pathological changes in the brain induced by DM. Diabetes-induced brain injury manifests as neurodegeneration, cerebral infarction, and progressive cognitive decline.…”

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

“…Previous studies found numerous lncRNAs through microarray and RNA-seq that are crucial for the development of various diseases, especially malignant tumors 30 - 32 . According to the NCBI database, MEG3 is located on chromosome 14q32.3 in Homo sapiens and functions as a tumor suppressor in many cancers 33 , 34 .…”