Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Int J Cardiol. 2021 May 15;331:189-198. doi: 10.1016/j.ijcard.2021.01.036. Epub 2021 Jan 31.
Endothelial dysfunction is a key event in the development of vascular diseases, including atherosclerosis. Endothelial progenitor cells (EPCs) play an important role in vascular repair. Decreased dimethylarginine dimethylaminohydrolase (DDAH) activity is observed in several pathological conditions, and it is associated with an increased risk of vascular disease. We hypothesized that bone marrow-derived EPCs and combination therapy with DDAH2-EPCs could reduce plaque size and ameliorate endothelial dysfunction in an atherosclerosis rabbit model.
Four groups of rabbits (n = 8 per group) were subjected to a hyperlipidemic diet for a month. After establishing the atherosclerosis model, rabbits received 4 × 10 EPC, EPCs expressing DDAH2, through femoral vein injection, or saline (the control group with basic food and the untreated group). One month after transplantation, plaque thickness, endothelial function, oxidative stress, and inflammatory mRNAs, DDAH, and eNOS function were assessed.
DDAH2-EPCs transplantation (p < 0.05) and EPCs transplantation (p < 0.05) were both associated with a reduction in plaque size compared to the control saline injection. The antiproliferative and antiatherogenic effects of EPCs were further enhanced by the overexpression of DDAH2 (p < 0.05, DDAH2-EPCs vs. EPCs). Furthermore, DDAH2-EPCs transplantation significantly increased endothelium integrity compared to the EPCs transplantation.
Transplantation of EPCs overexpressing DDAH2 may enhance the repair of injured endothelium by reducing inflammation and restoring endothelial function. Therefore, pCMV6-mediated DDAH2 gene-transfected EPCs are a potentially valuable tool for the treatment of atherosclerosis.
内皮功能障碍是血管疾病（包括动脉粥样硬化）发展过程中的一个关键事件。内皮祖细胞（EPCs）在血管修复中起着重要作用。在几种病理条件下观察到二甲基精氨酸二甲胺水解酶（DDAH）活性降低，并且与血管疾病风险增加相关。我们假设骨髓源性 EPCs 和 DDAH2-EPCs 的联合治疗可以减少斑块大小并改善动脉粥样硬化兔模型中的内皮功能障碍。
四组兔子（每组 8 只）接受高脂饮食一个月。建立动脉粥样硬化模型后，通过股静脉注射 4×10 EPC、表达 DDAH2 的 EPC 或生理盐水（基础饮食对照组和未治疗组）。移植后 1 个月，评估斑块厚度、内皮功能、氧化应激和炎症 mRNAs、DDAH 和 eNOS 功能。
与对照组生理盐水注射相比，DDAH2-EPCs 移植（p<0.05）和 EPCs 移植（p<0.05）均与斑块大小减少相关。DDAH2 的过表达进一步增强了 EPCs 的抗增殖和抗动脉粥样硬化作用（p<0.05，DDAH2-EPCs 与 EPCs 相比）。此外，与 EPCs 移植相比，DDAH2-EPCs 移植显著增加了内皮完整性。
过表达 DDAH2 的 EPCs 移植可能通过减少炎症和恢复内皮功能来增强受损内皮的修复。因此，pCMV6 介导的 DDAH2 基因转染的 EPCs 是治疗动脉粥样硬化的一种有潜在价值的工具。
