Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy

Diabetes cardiomyopathy (DCM) is a critical complication of long-term chronic diabetes mellitus and is characterized by myocardial fibrosis and myocardial hypertrophy. It has been suggested that DCM is related to pyroptosis, a programmed cell death associated with inflammation. The long non-coding RNA Kcniq1ot1 is involved in different pathophysiological mechanisms of multiple diseases, including acute myocardial damage and arrhythmia. Our previous study found that Kcniq1ot1 was elevated in left ventricular tissue of diabetic mice. However, whether Kcniq1ot1 is capable of regulating pyroptosis and fibrosis in high glucose-treated cardiac fibroblasts remains unknown. The aim of the study was to investigate the mechanisms of Kcniq1ot1 in DCM. Our study revealed that silencing Kcniq1ot1 by a lentivirus-shRNA improved cardiac function and fibrosis, ameliorated pyroptosis, and inhibited TGF-beta 1/smalls pathway in C57BL/6 mice. In vitro, experiments revealed that Kcniq1ot1 and pyroptosis were activated in cardiac fibroblasts treated with 30 mmol/l glucose. Furthermore, Kcniq1ot1 knockdown by a small interfering RNA decreased caspase-1 expression. Bioinformatic prediction and luciferase assays showed that Kcniq1ot1 functioned as a competing endogenous RNA to regulate the expression of caspase-1 by sponging miR-214-3p. In addition, silencing Kcniq1ot1 promoted gasdermin D cleavage and the secretion of 1L-1 beta, thus repressing the TGF-beta 1/smads pathway in high glucose-treated cardiac fibroblasts through miR-214-3p and caspase-1. Therefore, Kcniq1ot1/miR-214-3p/caspase-1/TGF-beta 1 signal pathway presents a new mechanism of DCM progression and could potentially be a novel therapeutic target.