Department of Anatomy, Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu, 233000, Anhui, P.R. China.
Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu, 233000, Anhui, P.R. China.
BMC Cardiovasc Disord. 2024 Jul 10;24(1):351. doi: 10.1186/s12872-024-04010-x.
Diabetic cardiomyopathy (DCM) is a chronic disease caused by diabetes mellitus, which is recognized as a worldwide challenging disease. This study aimed to investigate the role and the potential mechanism of knocking down the NACHT-, LRR- and PYD domains-containing protein 3 (NLRP3), an inflammasome associated with onset and progression of various diseases, on high glucose or diabetes -induced cardiac cells pyroptosis and ferroptosis, two regulated non-necrosis cell death modalities discovered recent years. In the present study, both in vivo and in vitro studies were conducted simultaneously. Diabetic rats were induced by 55 mg/kg intraperitoneal injection of streptozotocin (STZ). Following the intraperitoneal injection of MCC950 (10 mg/kg), On the other hand, the DCM model in H9C2 cardiac cells was simulated with 35 mmol/L glucose and a short hairpin RNA vector of NLRP3 were transfected to cells. The results showed that in vivo study, myocardial fibers were loosely arranged and showed inflammatory cell infiltration, mitochondrial cristae were broken and the GSDMD-NT expression was found notably increased in the DM group, while the protein expressions of xCT and GPX4 was significantly decreased, both of which were reversed by MCC950. High glucose reduced the cell viability and ATP level in vitro, accompanied by an increase in LDH release. All of the above indicators were reversed after NLRP3 knockdown compared with the HG treated alone. Moreover, the protein expressions of pyroptosis- and ferroptosis-related fators were significantly decreased or increased, consistent with the results shown by immunofluorescence. Furthermore, the protective effects of NLRP3 knockdown against HG were reversed following the mtROS agonist rotenone (ROT) treatment. In conclusion, inhibition of NLRP3 suppressed DM-induced myocardial injury. Promotion of mitochondrial ROS abolished the protective effect of knockdown NLRP3, and induced the happening of pyroptosis and ferroptosis. These findings may present a novel therapeutic underlying mechanism for clinical diabetes-induced myocardial injury treatment.
糖尿病心肌病（DCM）是一种由糖尿病引起的慢性疾病，被认为是一种全球性的挑战性疾病。本研究旨在探讨含有 NACHT、LRR 和 PYD 结构域的蛋白 3（NLRP3）敲低在高糖或糖尿病诱导的心脏细胞细胞焦亡和铁死亡中的作用及其潜在机制，NLRP3 是一种与各种疾病的发生和进展相关的炎症小体。在本研究中，同时进行了体内和体外研究。通过腹腔注射 55mg/kg 链脲佐菌素（STZ）诱导糖尿病大鼠。另一方面，用 MCC950（10mg/kg）腹腔注射，另一方面，用 35mmol/L 葡萄糖模拟 H9C2 心肌细胞的 DCM 模型，并转染 NLRP3 的短发夹 RNA 载体。结果表明，在体内研究中，DM 组心肌纤维排列松散，出现炎症细胞浸润，线粒体嵴断裂，GSDMD-NT 表达明显增加，而 xCT 和 GPX4 的蛋白表达明显降低，这两种情况均被 MCC950 逆转。体外高糖降低细胞活力和 ATP 水平，同时 LDH 释放增加。与单独用 HG 处理相比，NLRP3 敲低后所有上述指标均逆转。此外，与单独用 HG 处理相比，细胞焦亡和铁死亡相关因子的蛋白表达显著降低或增加，与免疫荧光结果一致。此外，mtROS 激动剂鱼藤酮（ROT）处理逆转了 NLRP3 敲低对 HG 的保护作用。综上所述，抑制 NLRP3 可抑制 DM 诱导的心肌损伤。促进线粒体 ROS 会逆转 NLRP3 敲低的保护作用，并诱导细胞发生焦亡和铁死亡。这些发现可能为临床糖尿病诱导的心肌损伤治疗提供新的治疗机制。
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