Lin Yi-Wen, Huang Chun-Yao, Chen Yung-Hsiang, Shih Chun-Ming, Tsao Nai-Wen, Lin Cheng-Yen, Chang Nen-Chung, Tsai Chien-Sung, Tsai Hsiao-Ya, Tsai Jui-Chi, Huang Po-Hsun, Li Chi-Yuan, Lin Feng-Yen
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan ; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
PLoS One. 2013 Dec 23;8(12):e84731. doi: 10.1371/journal.pone.0084731. eCollection 2013.
The number and function of endothelial progenitor cells (EPCs) are sensitive to hyperglycemia, hypertension, and smoking in humans, which are also associated with the development of atherosclerosis. GroEL1 from Chlamydia pneumoniae has been found in atherosclerotic lesions and is related to atherosclerotic pathogenesis. However, the actual effects of GroEL1 on EPC function are unclear. In this study, we investigate the EPC function in GroEL1-administered hind limb-ischemic C57BL/B6 and C57BL/10ScNJ (a toll-like receptor 4 (TLR4) mutation) mice and human EPCs. In mice, laser Doppler imaging, flow cytometry, and immunohistochemistry were used to evaluate the degree of neo-vasculogenesis, circulating level of EPCs, and expression of CD34, vWF, and endothelial nitric oxide synthase (eNOS) in vessels. Blood flow in the ischemic limb was significantly impaired in C57BL/B6 but not C57BL/10ScNJ mice treated with GroEL1. Circulating EPCs were also decreased after GroEL1 administration in C57BL/B6 mice. Additionally, GroEL1 inhibited the expression of CD34 and eNOS in C57BL/B6 ischemic muscle. In vitro, GroEL1 impaired the capacity of differentiation, mobilization, tube formation, and migration of EPCs. GroEL1 increased senescence, which was mediated by caspases, p38 MAPK, and ERK1/2 signaling in EPCs. Furthermore, GroEL1 decreased integrin and E-selectin expression and induced inflammatory responses in EPCs. In conclusion, these findings suggest that TLR4 and impaired NO-related mechanisms could contribute to the reduced number and functional activity of EPCs in the presence of GroEL1 from C. pneumoniae.
内皮祖细胞（EPCs）的数量和功能对人类的高血糖、高血压和吸烟敏感，这些因素也与动脉粥样硬化的发展有关。肺炎衣原体的GroEL1已在动脉粥样硬化病变中被发现，并且与动脉粥样硬化的发病机制有关。然而，GroEL1对EPC功能的实际影响尚不清楚。在本研究中，我们研究了给予GroEL1的后肢缺血C57BL/B6和C57BL/10ScNJ（一种Toll样受体4（TLR4）突变）小鼠以及人类EPCs中的EPC功能。在小鼠中，使用激光多普勒成像、流式细胞术和免疫组织化学来评估新生血管形成的程度、EPCs的循环水平以及血管中CD34、vWF和内皮型一氧化氮合酶（eNOS）的表达。在用GroEL1处理的C57BL/B6小鼠中，缺血肢体的血流明显受损，但C57BL/10ScNJ小鼠未出现这种情况。在C57BL/B6小鼠中给予GroEL1后，循环EPCs也减少。此外，GroEL1抑制了C57BL/B6缺血肌肉中CD34和eNOS的表达。在体外，GroEL1损害了EPCs的分化、动员、管形成和迁移能力。GroEL1增加了衰老，这是由EPCs中的半胱天冬酶、p38丝裂原活化蛋白激酶和ERK1/2信号介导的。此外，GroEL1降低了整合素和E-选择素的表达，并在EPCs中诱导了炎症反应。总之，这些发现表明，在存在肺炎衣原体的GroEL1的情况下，TLR4和受损的NO相关机制可能导致EPCs数量减少和功能活性降低。
