Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai, 200092, China.
Department of Nutriology, Fudan University Shanghai Cancer Center, 270, Dong'An Road, Shanghai, 200032, China.
Biochem Biophys Res Commun. 2020 Jul 30;528(3):545-553. doi: 10.1016/j.bbrc.2020.05.151. Epub 2020 Jun 3.
Diabetic cardiomyopathy (DCM) is one of the main causes of heart failure in patients with diabetes. Cardiac fibrosis caused by endothelial mesenchymal transformation (EndMT) plays an important role in the pathogenesis of DCM. NLRC5 is a recently discovered immune and inflammatory regulatory molecule in the NOD-like receptor family, and is involved in organ fibrosis. In this study, we found that the expression of NLRC5 was up-regulated in endothelial cells (ECs) and cardiac fibroblasts (CFs) in diabetes models both in vivo and in vitro. NLRC5 knockdown significantly inhibited high glucose-induced EndMT. In addition, NLRC5 deficiency inhibited the expression of phosphorylated Smad2/3 and the activation of EndMT-related transcription factors in ECs induced by high glucose. However, the effect of NLRC5 deficiency on CFs was not obvious. In summary, our results suggest that NLRC5 deficiency ameliorates cardiac fibrosis in DCM by inhibiting EndMT through Smad2/3 signaling pathway and related transcription factors. NLRC5 is likely to be a biomarker and therapeutic target of cardiac fibrosis in diabetic cardiomyopathy.
糖尿病心肌病（DCM）是糖尿病患者心力衰竭的主要原因之一。内皮间质转化（EndMT）引起的心脏纤维化在 DCM 的发病机制中起重要作用。NLRC5 是 NOD 样受体家族中最近发现的免疫和炎症调节分子，参与器官纤维化。在本研究中，我们发现 NLRC5 的表达在体内和体外糖尿病模型的内皮细胞（ECs）和心肌成纤维细胞（CFs）中均上调。NLRC5 敲低显著抑制高糖诱导的 EndMT。此外，NLRC5 缺乏抑制高糖诱导的 ECs 中磷酸化 Smad2/3 和 EndMT 相关转录因子的表达。然而，NLRC5 缺乏对 CFs 的作用不明显。总之，我们的结果表明，NLRC5 缺乏通过 Smad2/3 信号通路和相关转录因子抑制 EndMT 改善 DCM 中的心脏纤维化。NLRC5 可能是糖尿病心肌病中心脏纤维化的生物标志物和治疗靶点。
