Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China.
Cell Signal. 2024 Oct;122:111333. doi: 10.1016/j.cellsig.2024.111333. Epub 2024 Aug 3.
PIWI-interacting RNAs (piRNAs) are involved in the regulation of hypertrophic cardiomyopathy, heart failure and myocardial methylation. However, their functions and the underlying molecular mechanisms in diabetic cardiomyopathy (DCM) have yet to be fully elucidated. In the present study, a pyroptosis-associated piRNA (piR112710) was identified that ameliorates cardiac remodeling through targeting the activation of inflammasomes and mitochondrial dysfunction that are mediated via the thioredoxin-interacting protein (Txnip)/NLRP3 signaling axis. Subsequently, the cardioprotective effects of piR112710 on both the myocardium from db/db mice and cardiomyocytes from neonatal mice that were incubated with a high concentration of glucose combined with palmitate were examined. piR112710 was found to significantly improve cardiac dysfunction in db/db mice, characterized by improved echocardiography, lower levels of fibrosis, attenuated expression levels of inflammatory factors and pyroptosis-associated proteins (namely, Txnip, ASC, NLRP3, caspase-1 and GSDMD-N), and enhanced myocardial mitochondrial respiratory functions. In cultured neonatal mice cardiomyocytes, piR112710 deficiency and high glucose along with palmitate treatment led to significantly upregulated expression levels of pyroptosis associated proteins and collagens, oxidative stress, mitochondrial dysfunction and increased levels of inflammatory factors. Supplementation with piR112710, however, led to a reversal of the aforementioned changes induced by high glucose and palmitate. Mechanistically, the cardioprotective effect of piR112710 appears to be dependent upon effective elimination of reactive oxygen species and inactivation of the Txnip/NLRP3 signaling axis. Taken together, the findings of the present study have revealed that the piRNA-mediated inhibitory mechanism involving the Txnip/NLRP3 axis may participate in the regulation of pyroptosis, which protects against DCM both in vivo and in vitro. piR112710 may therefore be a potential therapeutic target for the reduction of myocardial injury caused by cardiomyocyte pyroptosis in DCM.
PIWI 相互作用 RNA（piRNA）参与调控肥厚型心肌病、心力衰竭和心肌甲基化。然而，它们在糖尿病心肌病（DCM）中的功能和潜在分子机制尚未完全阐明。在本研究中，鉴定出一种与细胞焦亡相关的 piRNA（piR112710），其通过靶向激活炎症小体和线粒体功能障碍，从而减轻心脏重构，而炎症小体和线粒体功能障碍是通过硫氧还蛋白相互作用蛋白（Txnip）/NLRP3 信号轴介导的。随后，研究了 piR112710 对 db/db 小鼠心肌和高浓度葡萄糖联合棕榈酸孵育的新生小鼠心肌细胞的心脏保护作用。结果发现，piR112710 可显著改善 db/db 小鼠的心脏功能障碍，表现为超声心动图改善、纤维化程度降低、炎症因子和细胞焦亡相关蛋白（即 Txnip、ASC、NLRP3、caspase-1 和 GSDMD-N）表达水平降低以及心肌线粒体呼吸功能增强。在培养的新生小鼠心肌细胞中，piR112710 缺乏和高葡萄糖联合棕榈酸处理导致细胞焦亡相关蛋白和胶原表达水平显著上调、氧化应激、线粒体功能障碍和炎症因子水平升高。然而，补充 piR112710 可逆转高葡萄糖和棕榈酸引起的上述变化。机制上，piR112710 的心脏保护作用似乎依赖于有效清除活性氧和抑制 Txnip/NLRP3 信号轴。综上所述，本研究结果表明，piRNA 介导的 Txnip/NLRP3 轴抑制机制可能参与了细胞焦亡的调节，从而在体内和体外均能保护 DCM。piR112710 因此可能成为减少 DCM 中心肌细胞细胞焦亡引起的心肌损伤的潜在治疗靶点。
