CDC42 promotes vascular calcification in chronic kidney disease
CDC42 promotes vascular calcification in chronic kidney disease
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CDC42促进慢性肾脏病的血管钙化
DOI：
10.1002/path.5334
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发表时间：
2019-10-01
影响因子：
7.3
通讯作者：
Chen, Minsheng
中科院分区：
文献类型：
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作者：
Li, Zehua;Wu, Ji;Chen, Minsheng
血管钙化在慢性肾脏病（CKD）患者中普遍存在，是心血管疾病的主要危险因素。血管钙化被认为是一个类似于骨形成的生物学过程，涉及血管平滑肌细胞（VSMCs）的成骨分化。细胞分裂周期42（CDC 42）是Rac 1家族成员之一，在软骨内成骨过程中对软骨发育至关重要。然而，CDC 42是否影响VSMCs的成骨分化和血管钙化仍不清楚。在本研究中，我们观察到在大鼠血管平滑肌细胞和钙化的动脉血管钙化过程中，CDC 42的表达显着增加。茜素红染色和钙含量测定显示，腺病毒介导的CDC 42过表达导致VSMC在钙化培养基存在下明显钙化，并伴有骨相关分子包括RUNX 2和BMP 2的上调。相比之下，ML 141抑制CDC 42可显著阻断体外VSMCs钙化和离体主动脉环钙化。此外，ML 141显著减弱CKD大鼠的血管钙化。此外，AKT信号的药理学抑制显示阻断CDC 42诱导的VSMC钙化。这些发现首次证明了CDC 42通过涉及AKT信号传导的机制促进血管钙化;这揭示了CDC 42在调节血管钙化中的新功能。这可能为CKD背景下血管钙化的治疗提供潜在的治疗靶点。© 2019大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
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.