Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which can result in cardiac hypertrophy and subsequent heart failure, associated with pyroptosis, the pro-inflammatory programmed cell death. MicroRNAs (miRNAs), small endogenous non-coding RNAs, have been shown to be involved in diabetic cardiomyopathy. However, whether miRNAs regulate pyroptosis in diabetic cardiomyopathy remains unknown. Our study revealed that mir-30d expression was substantially increased in streptozotocin (STZ)-induced diabetic rats and in high-glucose-treated cardiomyocytes as well. Upregulation of mir-30d promoted cardiomyocyte pyroptosis in diabetic cardiomyopathy; conversely, knockdown of mir-30d attenuated it. In an effort to understand the signaling mechanisms underlying the pro-pyroptotic property of mir-30d, we found that forced expression of mir-30d upregulated caspase-1 and pro-inflammatory cytokines IL-1β and IL-18. Moreover, mir-30d directly repressed foxo3a expression and its downstream protein, apoptosis repressor with caspase recruitment domain (ARC). Furthermore, silencing ARC by siRNA mimicked the action of mir-30d: upregulating caspase-1 and inducing pyroptosis. These findings promoted us to propose a new signaling pathway leading to cardiomyocyte pyroptosis under hyperglycemic conditions: mir-30d↑→foxo3a↓→ ARC↓→caspase-1↑→IL-1β, IL-18↑→pyroptosis↑. Therefore, mir-30d may be a promising therapeutic target for the management of diabetic cardiomyopathy.
Background: As reliable intercellular transporters, exosomes for the diagnosis and function of various disease are fully explored. Also, exosomes extracted from tear film have been used as indictors for various eye disease, even systemic disease due to the easy and non-invasive collection nature with microRNAs variation. However, there still no reports focus the change and function of on exosomes and exosomal microRNAs during diabetes ocular dysfunction.Methods: Paired diabetes and health tear film-derived exosomes were collected by test strips and identified according standard regimens. Different expression microRNAs were profiled by microarray. The function of exosomes to cornea epithelium was detected by cornea wound model in vivo and cell viability and migration assay in vitro. Bioinformatics analysis, including GO and KEGG were conducted to explore the potential biological signaling pathway.Results: We confirmed diabetic tear film derived exosomes contribute to delay cornea wound healing and aggravate diabetic dry eye-like syndrome. Total 12 differential expression microRNAs were confirmed compared with paired controls, may participate in glycosphingolipid biosynthesis; mucin type O-Glycan biosynthesis; Ras signaling pathway; AMPK signaling pathway; bacterial invasion of epithelial cells; ErbB signaling pathway; cGMP-PKG signaling pathwayConclusion: This study provides evidence that diabetic tear film derived exosomes can affect the ocular surface health during diabetes, while healthy exosomes have no similar effects. Thus, the different expression of microRNAs existed in the exosomes from diabetes and healthy volunteer may be the reason of different function.
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