LncRNA MEG3 exacerbates diabetic cardiomyopathy via activating pyroptosis signaling pathway

<b>Background:</b> Diabetic cardiomyopathy (DCM) is a prevalent complication observed in diabetic patients. The long non-coding RNA maternally expressed gene 3 (<i>lncMEG3</i>) has been found to be intricately associated with myocardial infarction and heart failure. However, the role of <i>lncMEG3</i> in DCM remains unclear. The present study was designed to investigate the role of <i>lncMEG3</i> in DCM and elucidate the underlying molecular mechanisms. <b>Methods:</b> The diabetic mouse model was established through intraperitoneal injection streptozotocin (STZ). The heart-targeted adeno-associated virus carrying <i>lncMEG3</i> interfering RNA (AAV9-shMEG3) was administered via tail-vein injection to induce silencing of <i>lncMEG3</i> in diabetic mice. Echocardiography was performed to evaluate cardiac function, while hematoxylin and eosin (H&E) staining and Masson trichrome staining were employed for the detection of cardiac remodeling. The underlying mechanisms were investigated using Western blot and real-time PCR (qPCR). <b>Results:</b> The expression of <i>lncMEG3</i> was increased in hearts with DCM and in AC16 cardiomyocytes treated with high glucose. The knockout of <i>lncMEG3</i> reduced inflammation, cardiac fibrosis and myocardial hypertrophy, and improved cardiac dysfunction in diabetic mice. In diabetic mice, the activation of the nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3)-inflammasome was observed, whereas silencing of <i>lncMEG3</i> resulted in a reduction in NLRP3 inflammasome activation. Mechanistically, we discovered that <i>lncMEG3</i> specifically functions as a competitive inhibitor of <i>miR-223</i>. Moreover, the use of <i>miR-223</i> antisense oligonucleotide (AMO) counteracted the suppressive effects of <i>lncMEG3</i> knockdown on NLRP3 inflammasome activation induced by high glucose <i>in vitro</i>. <b>Conclusion:</b> <i>LncMEG3</i> exacerbates DCM by enhancing NLRP3 inflammasome activation through attenuating <i>miR-223</i>-mediated degradation of NLRP3 in the hearts of individuals with diabetes.