Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China; University of Hull, Hull HU6 7RX, United Kingdom.
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China; Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan 250012, China.
J Biol Chem. 2019 May 17;294(20):8218-8226. doi: 10.1074/jbc.RA119.007648. Epub 2019 Apr 5.
Excessive activation of the renin-angiotensin system (RAS) in diabetic cardiomyopathy (DCM) provokes a series of structural and functional abnormalities, and causes ventricular remodeling and heart failure in diabetes. (Pro)renin receptor (PRR) is a component of the RAS and has been reported to be up-regulated in some cardiovascular diseases. Furthermore, PRR blockade in some cardiovascular diseases, such as myocardial infarction and hypertension, has been demonstrated to reverse their pathogenesis. However, there have been few studies about the function of PRR in the pathogenesis of DCM. In this study, we hypothesized that PRR is involved in the pathogenesis of DCM and mediates myocardial injury in DCM. To explore the role of PRR in DCM, we evaluated the effects of PRR overexpression and knockdown on the DCM phenotype and The results show that PRR overexpression exacerbates myocardial injury and the inflammatory response in rats with DCM. Conversely, PRR knockdown alleviates myocardial fibrosis, apoptosis, and the inflammatory response, reversing the cardiac dysfunction in rats with DCM. In cell experiments, PRR overexpression also up-regulated the protein expression of collagen I and fibronectin, aggravated the inflammatory response, and increased the production of reactive oxygen species, whereas PRR knockdown had the opposite effect. Thus, PRR mediates myocardial injury, apoptosis, and the inflammatory response, likely through a PRR/extracellular signal-regulated kinase/reactive oxygen species pathway.
在糖尿病心肌病（DCM）中，肾素-血管紧张素系统（RAS）过度激活会引发一系列结构和功能异常，并导致糖尿病患者的心室重构和心力衰竭。（前）肾素受体（PRR）是 RAS 的一个组成部分，据报道在一些心血管疾病中其表达上调。此外，在一些心血管疾病（如心肌梗死和高血压）中，PRR 阻断已被证明可以逆转其发病机制。然而，关于 PRR 在 DCM 发病机制中的作用的研究甚少。在这项研究中，我们假设 PRR 参与 DCM 的发病机制，并介导 DCM 中的心肌损伤。为了探讨 PRR 在 DCM 中的作用，我们评估了 PRR 过表达和敲低对 DCM 表型的影响。结果表明，PRR 过表达加剧了 DCM 大鼠的心肌损伤和炎症反应。相反，PRR 敲低减轻了心肌纤维化、凋亡和炎症反应，逆转了 DCM 大鼠的心脏功能障碍。在细胞实验中，PRR 过表达也上调了胶原 I 和纤维连接蛋白的蛋白表达，加重了炎症反应，增加了活性氧的产生，而 PRR 敲低则产生相反的效果。因此，PRR 通过 PRR/细胞外信号调节激酶/活性氧途径介导心肌损伤、凋亡和炎症反应。
