Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis
Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis
复制标题
靶向抑制内皮钙蛋白酶通过减少炎症和血管生成来延迟伤口愈合
DOI：
10.1038/s41419-020-02737-x
复制
发表时间：
2020-07-14
影响因子：
9
通讯作者：
Teng，Xiaomei
中科院分区：
文献类型：
--
作者：
Yi，Chenlong;Wu，Weihua;Teng，Xiaomei
伤口愈合是一个多步骤的现象，依赖于各种细胞类型之间复杂的相互作用。钙蛋白酶是一种众所周知的钙依赖性半胱氨酸蛋白酶家族，它调节多种过程，包括细胞粘附、增殖、迁移、炎症和血管生成。CAPNS1是Calpain-1和calpain - 2的共同调控亚基，对于催化亚基的稳定和活性是不可或缺的。钙蛋白酶抑制已被证明可以减少各种疾病模型中的器官损伤。在这里，我们报道内皮细胞calpain-1/2在皮肤伤口愈合中起着至关重要的作用。使用仅在内皮细胞中删除ecapns1的小鼠遗传模型，我们发现calpain-1/2破坏与损伤激活炎症减少、CD31+血管密度降低和伤口愈合延迟有关。此外，在培养的HUVECs中，抑制calpain可降低TNF-α-诱导的增殖、迁移和管形成。capns1的缺失与内皮细胞中i - κ b水平升高和β-catenin表达下调有关。这些观察结果描述了钙蛋白酶在皮肤修复过程中炎症和血管生成之间的相互作用中的一种新的机制作用。
Wound healing is a multistep phenomenon that relies on complex interactions between various cell types. Calpains are a well-known family of calcium-dependent cysteine proteases that regulate several processes, including cellular adhesion, proliferation, and migration, as well as inflammation and angiogenesis. CAPNS1, the common regulatory subunit of Calpain-1 and 2, is indispensable for catalytic subunit stabilization and activity. Calpain inhibition has been shown to reduce organ damage in various disease models. Here, we report that endothelial calpain-1/2 is crucially involved in skin wound healing. Using a mouse genetic model whereCapns1is deleted only in endothelial cells, we showed that calpain-1/2 disruption is associated with reduced injury-activated inflammation, reduced CD31+blood vessel density, and delayed wound healing. Moreover, in cultured HUVECs, inhibition of calpain reduced TNF-α-induced proliferation, migration, and tube formation. Deletion ofCapns1was associated with elevated levels of IκB and downregulation of β-catenin expression in endothelial cells. These observations delineate a novel mechanistic role for calpain in the crosstalk between inflammation and angiogenesis during skin repair.