Abstract
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.
Highlights
The skin is the largest organ of the human body and acts as a protective barrier against external stimuli and pathogen invasion
Deficiency of endothelial cell Capns[1] delays wound healing of dorsal skin To evaluate the effects of endothelial cell-specific calpain-1/2 disruption following skin injury, full-thickness 15 mm diameter excisional wounds were made on TEKCRE+/− Capns1PZ/PZ (KO) mice and their wild-type (WT) littermates, and the wounds were monitored for 7 days
Morphometric analyses of wound sections (Fig. 1c–h) displayed a delay in wound closure in KO mice by quantification of the distance of newly formed epidermis covering the wound, an average of 39.74% of the wound was covered by epidermis in control mice, while only 29.40% of the wound was covered in Capns1-KO mice at the same timepoint (Fig. 1c, g, h)
Summary
The skin is the largest organ of the human body and acts as a protective barrier against external stimuli and pathogen invasion. Skin wound healing undergoes multiple overlapping phases, including a peak angiogenic response after injury, followed by decreased vessel numbers upon wound closure and simultaneously fibrosis and scarring[2]. These repair mechanisms involve in elaborate and intricate processes and remain incompletely understood[3]. Calpain-1/2 isoforms are heterodimers consisting of CAPN1 and CAPN2 catalytic subunits, respectively, and the common small regulatory subunit CAPNS1, known as CAPN4. These ubiquitous classical calpain isoforms are regulated by the endogenous calpainspecific inhibitor, calpastatin (CAST). Inhibiting calpain activity has been shown to reduces tissue damage in experimental models of inflammatory diseases[7], cancer
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