Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis

• Published in: Cell death & disease Vol. 11; no. 7; p. 533
• Main Authors: Yi, Chenlong, Wu, Weihua, Zheng, Dong, Peng, Guangying, Huang, Haoyue, Shen, Zhenya, Teng, Xiaomei
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 14.07.2020; Nature Publishing Group UK
• Subjects: Angiogenesis; Animals; Calcium; Calpain; Calpain - antagonists & inhibitors; Cell Proliferation; Endothelial cells; Humans; Inflammation; Inflammation - drug therapy; Mice; Neovascularization, Pathologic - drug therapy; Tumor necrosis factor-α; Wound healing; Wound Healing - drug effects; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02737-x

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 where Capns1 is 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 of Capns1 was 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.