FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes.
FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes.
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DOI：
10.1161/circresaha.121.319066
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发表时间：
2021-12-03
影响因子：
20.1
通讯作者：
Lim SS
中科院分区：
文献类型：
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作者：
Jeong K;Murphy JM;Kim JH;Campbell PM;Park H;Rodriguez YAR;Choi CS;Kim JS;Park S;Kim HJ;Scammell JG;Weber DS;Honkanen RE;Schlaepfer DD;Ahn EE;Lim SS
血管平滑肌细胞（SMC）表现出显著的可塑性，并可在与疾病和干预相关的病理刺激下发生去分化。虽然表观遗传变化是至关重要的SMC表型转换，一个基本的调节器，管理表观遗传机制调节SMC表型的命运还没有得到阐明。利用SMC、小鼠模型和人动脉粥样硬化标本，我们发现粘着斑激酶（FAK）激活通过稳定DNA甲基转移酶3A（DNMT 3A）促进SMC去分化。SMC中的FAK在体外血清刺激或血管损伤时在细胞质中被激活，并且活性FAK防止DNMT 3A免于核FAK介导的降解。然而，药理学或遗传FAK催化抑制迫使FAK核定位，这通过增强泛素化和蛋白酶体降解减少DNMT 3A蛋白。DNMT 3A蛋白减少导致收缩基因启动子DNA低甲基化，从而增加SMC收缩蛋白的表达。RNA测序鉴定SMC收缩基因为与载体组相比通过来自损伤的股动脉样品的FAK抑制最先上调的组。DNMT3A在受损动脉中的敲低降低了DNA甲基化并增强了收缩基因表达，这支持了核FAK介导的DNMT3A通过E3连接酶TRAF6降解驱动SMC分化的观点。此外，我们观察到人动脉粥样硬化病变的SMC表现出减少的核FAK，这与增加的DNMT 3A水平和减少的收缩基因表达有关。本研究表明，FAK催化抑制诱导的核FAK特异性抑制损伤血管中DNMT 3A的表达，从而通过促进收缩基因表达维持SMC分化。因此，FAK抑制剂可能为阻断血管重塑和动脉粥样硬化过程中SMC表型转换提供一种新的治疗选择。
Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions. Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated. Using SMCs, mouse models, and human atherosclerosis specimens, we found that focal adhesion kinase (FAK) activation elicits SMC dedifferentiation by stabilizing DNA methyltransferase 3A (DNMT3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared to vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression. This study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.