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 Kcnq1ot1 is involved in different pathophysiological mechanisms of multiple diseases, including acute myocardial damage and arrhythmia. Our previous study found that Kcnq1ot1 was elevated in left ventricular tissue of diabetic mice. However, whether Kcnq1ot1 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 Kcnq1ot1 in DCM. Our study revealed that silencing Kcnq1ot1 by a lentivirus-shRNA improved cardiac function and fibrosis, ameliorated pyroptosis, and inhibited TGF-β1/smads pathway in C57BL/6 mice. In vitro, experiments revealed that Kcnq1ot1 and pyroptosis were activated in cardiac fibroblasts treated with 30 mmol/l glucose. Furthermore, Kcnq1ot1 knockdown by a small interfering RNA decreased caspase-1 expression. Bioinformatic prediction and luciferase assays showed that Kcnq1ot1 functioned as a competing endogenous RNA to regulate the expression of caspase-1 by sponging miR-214-3p. In addition, silencing Kcnq1ot1 promoted gasdermin D cleavage and the secretion of IL-1β, thus repressing the TGF-β1/smads pathway in high glucose-treated cardiac fibroblasts through miR-214-3p and caspase-1. Therefore, Kcnq1ot1/miR-214-3p/caspase-1/TGF-β1 signal pathway presents a new mechanism of DCM progression and could potentially be a novel therapeutic target.

糖尿病心肌病（DCM）是长期慢性糖尿病的一种严重并发症，其特征为心肌纤维化和心肌肥大。有人提出，DCM与细胞焦亡有关，细胞焦亡是一种与炎症相关的程序性细胞死亡。长链非编码RNA Kcnq1ot1参与多种疾病的不同病理生理机制，包括急性心肌损伤和心律失常。我们先前的研究发现，Kcnq1ot1在糖尿病小鼠的左心室组织中升高。然而，Kcnq1ot1是否能够调节高糖处理的心脏成纤维细胞中的细胞焦亡和纤维化仍然未知。本研究的目的是探讨Kcnq1ot1在DCM中的作用机制。我们的研究表明，用慢病毒 - shRNA沉默Kcnq1ot1可改善C57BL/6小鼠的心功能和纤维化，减轻细胞焦亡，并抑制TGF - β1/smads通路。在体外实验中，发现用30 mmol/L葡萄糖处理的心脏成纤维细胞中Kcnq1ot1和细胞焦亡被激活。此外，用小干扰RNA敲低Kcnq1ot1可降低caspase - 1的表达。生物信息学预测和荧光素酶实验表明，Kcnq1ot1作为一种竞争性内源性RNA，通过吸附miR - 214 - 3p来调节caspase - 1的表达。此外，沉默Kcnq1ot1促进了gasdermin D的裂解和IL - 1β的分泌，从而通过miR - 214 - 3p和caspase - 1抑制高糖处理的心脏成纤维细胞中的TGF - β1/smads通路。因此，Kcnq1ot1/miR - 214 - 3p/caspase - 1/TGF - β1信号通路为DCM的进展提供了一种新的机制，并可能成为一个新的治疗靶点。