Department of Endocrinology and Metabolism, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
Department of Endocrinology and Metabolism, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
Life Sci. 2020 Sep 1;256:117980. doi: 10.1016/j.lfs.2020.117980. Epub 2020 Jun 16.
Diabetic cardiomyopathy (DCM) is an independent and specific cardiomyopathy, which is associated with cardiac failure in diabetic patients. Currently, the pathogenesis of DCM is a popular research topic in the investigation of cardiovascular diseases. MicroRNAs (miRNAs) have been identified as the latent therapeutic targets for DCM. However, the functions and complex mechanisms of miRNAs in DCM have not been clarified. The cardiomyocyte injury model was established using high glucose (HG) ingestion, and the DCM rat model was established using 30 mg/kg streptozotocin. MicroRNA-223 (miR-223) expression was determined using qRT-PCR; the levels of NLRP3 inflammasome, fibrosis, and apoptosis-related genes and proteins were analyzed using qRT-PCR and western blot assays. Besides the morphological changes and fibrosis of myocardial tissues were evaluated using H&E and Masson staining. We discovered that miR-223 was highly expressed in the HG-induced cardiomyocyte injury model, and miR-223 inhibitor could further relieve the myocardial fibrosis and apoptosis, and inhibit NLRP3 inflammasome of HG-induced H9c2 cells. Additionally, we found that inhibition of miR-223 had obvious positive effects on the cardiac dysfunction and reduced the elevation of blood sugar in the DCM model rats. We found that the miRNA-223 inhibitor could improve the morphological structure and the degree of fibrosis in myocardial tissues in the DCM model rats. Moreover, we verified that inhibition of miR-223 could suppress the NLRP3 inflammasome activation, and alleviate myocardial fibrosis and apoptosis of the DCM model rats. In conclusion, our results suggested that miR-223 might be an underlying therapeutic target for DCM by reducing NLRP3 inflammasome activation, fibrosis, and apoptosis.
糖尿病心肌病（DCM）是一种独立且特异的心肌病，与糖尿病患者的心衰有关。目前，DCM 的发病机制是心血管疾病研究的热门课题。microRNAs（miRNAs）已被确定为 DCM 的潜在治疗靶点。然而，miRNAs 在 DCM 中的功能和复杂机制尚未阐明。采用高糖（HG）摄入建立心肌细胞损伤模型，采用 30mg/kg 链脲佐菌素建立 DCM 大鼠模型。采用 qRT-PCR 测定 microRNA-223（miR-223）表达；采用 qRT-PCR 和 Western blot 检测 NLRP3 炎性体、纤维化和细胞凋亡相关基因和蛋白水平。此外，采用 H&E 和 Masson 染色评估心肌组织的形态变化和纤维化。我们发现 miR-223 在 HG 诱导的心肌细胞损伤模型中高表达，miR-223 抑制剂可进一步减轻 HG 诱导的 H9c2 细胞的心肌纤维化和细胞凋亡，抑制 NLRP3 炎性体。此外，我们发现抑制 miR-223 对 DCM 模型大鼠的心功能障碍有明显的积极作用，并降低血糖升高。我们发现 miRNA-223 抑制剂可改善 DCM 模型大鼠心肌组织的形态结构和纤维化程度。此外，我们验证了抑制 miR-223 可抑制 NLRP3 炎性体的激活，减轻 DCM 模型大鼠的心肌纤维化和细胞凋亡。总之，我们的研究结果表明，通过抑制 NLRP3 炎性体的激活，减轻纤维化和细胞凋亡，miR-223 可能成为 DCM 的潜在治疗靶点。
