Bai Weiwei, Cheng Meijuan, Jin Jingjing, Zhang Dongxue, Li Lanmei, Bai Yaling, Xu Jinsheng
Department of Nephrology, The Fourth Hospital of Hebei Medical University, Hebei Clinical Research Center for Chronic Kidney Disease, Hebei Key Laboratory of Vascular Calcification in Kidney Disease, Shijiazhuang, P.R. China.
Mol Biol Rep. 2023 Apr;50(4):3217-3228. doi: 10.1007/s11033-022-08225-z. Epub 2023 Jan 27.
Osteoblast phenotypic transition in vascular smooth muscle cells (VSMCs) has been unveiled as a common cause of vascular calcification (VC). Krüppel-Associated Box (KRAB)-Associated Protein 1(KAP1) is a transcriptional corepressor that modulates various intracellular pathological processes from gene expression to DNA repair to signal transduction. However, the function and mechanism of KAP1 on the osteoblastic differentiation of VSMCs have not been evaluated yet.
We demonstrate that the expression of KAP1 in VSMCs is significantly enhanced in vivo and in vitro calcification models. Downregulating the expression of KAP1 suppresses the osteoblast phenotypic transition of VSMCs, which is indicated by a decrease in the expression of osteoblast marker collagenase type I (COL I) and an increase in the expression of VSMC marker α-smooth muscle actin (α-SMA). Conversely, exogenous overexpression of KAP1 could promote osteoblast phenotypic transition of VSMCs. Moreover, KAP1 upregulated the expression of RUNX family transcription factor 2 (Runx2), an inducer of osteoblast that positively regulates many osteoblast-related genes, such as COL I. Evaluation of the potential mechanism demonstrated that KAP1 promoted osteoblast phenotypic transition of VSMCs by activating the extracellular regulated protein kinases (ERK) signaling pathway, which could activate Runx2. In support of this finding, KAP1-induced cell osteoblast phenotypic transition is abolished by treatment with PD0325901, a specific ERK inhibitor.
The present study suggested that KAP1 participated in the osteoblast differentiation of VSMCs via the ERK/Runx2 cascade and served as a potential diagnostics and therapeutics target for vascular calcification.
血管平滑肌细胞（VSMCs）中的成骨细胞表型转变已被揭示为血管钙化（VC）的常见原因。Krüppel相关盒（KRAB）相关蛋白1（KAP1）是一种转录共抑制因子，可调节从基因表达、DNA修复到信号转导的各种细胞内病理过程。然而，KAP1对VSMCs成骨细胞分化的功能和机制尚未得到评估。
我们证明，在体内和体外钙化模型中，VSMCs中KAP1的表达显著增强。下调KAP1的表达可抑制VSMCs的成骨细胞表型转变，这表现为成骨细胞标志物I型胶原酶（COL I）表达降低，VSMC标志物α-平滑肌肌动蛋白（α-SMA）表达增加。相反，外源性过表达KAP1可促进VSMCs的成骨细胞表型转变。此外，KAP1上调了RUNX家族转录因子2（Runx2）的表达，Runx2是一种成骨细胞诱导剂，可正向调节许多成骨细胞相关基因，如COL I。对潜在机制的评估表明，KAP1通过激活细胞外调节蛋白激酶（ERK）信号通路促进VSMCs的成骨细胞表型转变，该信号通路可激活Runx2。支持这一发现的是，用特异性ERK抑制剂PD0325901处理可消除KAP1诱导的细胞成骨细胞表型转变。
本研究表明，KAP1通过ERK/Runx2级联反应参与VSMCs的成骨细胞分化，并作为血管钙化的潜在诊断和治疗靶点。
