A Novel Circular RNA Mediates Pyroptosis of Diabetic Cardiomyopathy by Functioning as a Competing Endogenous RNA

Diabetic cardiomyopathy (DCM) is a vital cause of fatalities in diabetic patients. The programmed death of cardiomyocytes and inflammation critically contribute to cardiac hypertrophy and fibrosis in DCM. Furthermore, circular RNA (circRNA) is a key regulator of various diseases. However, the role of circRNAs inDCMremains to be elucidated. Our previous study found that pyroptosis was markedly activated in the cardiomyocytes subjected to high-glucose conditions, and miR-214-3p regulated the expression of caspase-1. The aim of this study was to elucidate whether circRNA is involved in DCM pyroptosis via the miR-214-3p/caspase-1 pathway. Herein, we identified that hsa_circ_0076631, named caspase-1-associated circRNA (CACR), was increased both in high-glucose-treated cardiomyocytes and in the serum of diabetic patients. CACR also sponged an endogenous miR-214-3p to sequester and inhibit its expression. CACR knockdown in cardiomyocytes counteracted high-glucose-induced caspase-1 activation. Conversely, miR-214-3p knockdown partially abolished the beneficial effects of CACR silencing on pyroptosis in cardiomyocytes. Therefore, this study elucidated that CACRmight be a novel therapeutic target via the CACR/miR-214-3p/caspase-1 pathway in DCM.

糖尿病心肌病（DCM）是糖尿病患者死亡的一个重要原因。心肌细胞的程序性死亡和炎症对DCM中的心肌肥大和纤维化起着关键作用。此外，环状RNA（circRNA）是多种疾病的关键调节因子。然而，circRNA在DCM中的作用仍有待阐明。我们先前的研究发现，在高糖条件下的心肌细胞中，焦亡明显被激活，并且miR - 214 - 3p调节caspase - 1的表达。本研究的目的是阐明circRNA是否通过miR - 214 - 3p/caspase - 1通路参与DCM焦亡。在此，我们鉴定出hsa_circ_0076631（被命名为caspase - 1相关circRNA，即CACR）在高糖处理的心肌细胞以及糖尿病患者的血清中均增加。CACR还吸附内源性miR - 214 - 3p以隔离并抑制其表达。心肌细胞中CACR的敲低抵消了高糖诱导的caspase - 1激活。相反，miR - 214 - 3p的敲低部分消除了CACR沉默对心肌细胞焦亡的有益作用。因此，本研究阐明了CACR可能是DCM中通过CACR/miR - 214 - 3p/caspase - 1通路的一个新的治疗靶点。