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CDC42 promotes vascular calcification in chronic kidney disease.
The Journal of Pathology ( IF 7.3 ) Pub Date : 2019-10-01 , DOI: 10.1002/path.5334 Zehua Li 1, 2, 3 , Ji Wu 1, 2, 3 , Xiuli Zhang 1, 2, 3 , Caiwen Ou 1, 2, 3 , Xinglong Zhong 1, 2, 3 , Yanting Chen 4 , Lihe Lu 4 , Hailin Liu 1, 2, 3 , Yining Li 1, 2, 3 , Xiaoyu Liu 1, 2, 3 , Bo Wu 1, 2, 3 , Yuxi Wang 1, 2, 3 , Pingzhen Yang 1, 2, 3 , Jianyun Yan 1, 2, 3 , Minsheng Chen 1, 2, 3
The Journal of Pathology ( IF 7.3 ) Pub Date : 2019-10-01 , DOI: 10.1002/path.5334 Zehua Li 1, 2, 3 , Ji Wu 1, 2, 3 , Xiuli Zhang 1, 2, 3 , Caiwen Ou 1, 2, 3 , Xinglong Zhong 1, 2, 3 , Yanting Chen 4 , Lihe Lu 4 , Hailin Liu 1, 2, 3 , Yining Li 1, 2, 3 , Xiaoyu Liu 1, 2, 3 , Bo Wu 1, 2, 3 , Yuxi Wang 1, 2, 3 , Pingzhen Yang 1, 2, 3 , Jianyun Yan 1, 2, 3 , Minsheng Chen 1, 2, 3
Affiliation
Vascular calcification is prevalent in patients with chronic kidney disease (CKD) and a major risk factor of cardiovascular disease. Vascular calcification is now recognised as a biological process similar to bone formation involving osteogenic differentiation of vascular smooth muscle cells (VSMCs). Cell division cycle 42 (CDC42), a Rac1 family member GTPase, is essential for cartilage development during endochondral bone formation. However, whether CDC42 affects osteogenic differentiation of VSMCs and vascular calcification remains unknown. In the present study, we observed a significant increase in the expression of CDC42 both in rat VSMCs and in calcified arteries during vascular calcification. Alizarin red staining and calcium content assay revealed that adenovirus-mediated CDC42 overexpression led to an apparent VSMC calcification in the presence of calcifying medium, accompanied with up-regulation of bone-related molecules including RUNX2 and BMP2. By contrast, inhibition of CDC42 by ML141 significantly blocked calcification of VSMCs in vitro and aortic rings ex vivo. Moreover, ML141 markedly attenuated vascular calcification in rats with CKD. Furthermore, pharmacological inhibition of AKT signal was shown to block CDC42-induced VSMC calcification. These findings demonstrate for the first time that CDC42 contributes to vascular calcification through a mechanism involving AKT signalling; this uncovered a new function of CDC42 in regulating vascular calcification. This may provide a potential therapeutic target for the treatment of vascular calcification in the context of CKD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
中文翻译：
CDC42促进慢性肾脏疾病中的血管钙化。
血管钙化在患有慢性肾脏疾病（CKD）的患者中普遍存在，并且是心血管疾病的主要危险因素。血管钙化现已被认为是类似于骨骼形成的生物学过程，涉及血管平滑肌细胞（VSMC）的成骨分化。细胞分裂周期42（CDC42）是Rac1家族成员GTPase，对于软骨内骨形成过程中的软骨发育至关重要。然而，CDC42是否影响VSMCs的成骨分化和血管钙化仍然未知。在本研究中，我们观察到大鼠血管平滑肌细胞和钙化动脉中CDC42的表达在血管钙化过程中均显着增加。茜素红染色和钙含量测定显示，在钙化介质存在下，腺病毒介导的CDC42过表达导致明显的VSMC钙化，并伴有包括RUNX2和BMP2在内的骨相关分子的上调。相比之下，ML141对CDC42的抑制作用显着阻断了VSMC的钙化作用，离体主动脉环也被阻断。此外，ML141明显减轻了CKD大鼠的血管钙化。此外，对AKT信号的药理抑制作用被证明可以阻止CDC42诱导的VSMC钙化。这些发现首次证明CDC42通过涉及AKT信号传导的机制促进了血管钙化。这揭示了CDC42在调节血管钙化中的新功能。这可以为在CKD的情况下治疗血管钙化提供潜在的治疗靶标。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版
更新日期：2019-10-01
中文翻译：
CDC42促进慢性肾脏疾病中的血管钙化。
血管钙化在患有慢性肾脏疾病（CKD）的患者中普遍存在，并且是心血管疾病的主要危险因素。血管钙化现已被认为是类似于骨骼形成的生物学过程，涉及血管平滑肌细胞（VSMC）的成骨分化。细胞分裂周期42（CDC42）是Rac1家族成员GTPase，对于软骨内骨形成过程中的软骨发育至关重要。然而，CDC42是否影响VSMCs的成骨分化和血管钙化仍然未知。在本研究中，我们观察到大鼠血管平滑肌细胞和钙化动脉中CDC42的表达在血管钙化过程中均显着增加。茜素红染色和钙含量测定显示，在钙化介质存在下，腺病毒介导的CDC42过表达导致明显的VSMC钙化，并伴有包括RUNX2和BMP2在内的骨相关分子的上调。相比之下，ML141对CDC42的抑制作用显着阻断了VSMC的钙化作用，离体主动脉环也被阻断。此外，ML141明显减轻了CKD大鼠的血管钙化。此外，对AKT信号的药理抑制作用被证明可以阻止CDC42诱导的VSMC钙化。这些发现首次证明CDC42通过涉及AKT信号传导的机制促进了血管钙化。这揭示了CDC42在调节血管钙化中的新功能。这可以为在CKD的情况下治疗血管钙化提供潜在的治疗靶标。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版
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