Julovi, S.M.; McKelvey, K.; Minhas, N.; Chan, Y.-K.A.; Xue, M.; Jackson, C.J. Involvement of PAR-2 in the Induction of Cell-Specific Matrix Metalloproteinase-2 by Activated Protein C in Cutaneous Wound Healing. Int. J. Mol. Sci.2024, 25, 370.
Julovi, S.M.; McKelvey, K.; Minhas, N.; Chan, Y.-K.A.; Xue, M.; Jackson, C.J. Involvement of PAR-2 in the Induction of Cell-Specific Matrix Metalloproteinase-2 by Activated Protein C in Cutaneous Wound Healing. Int. J. Mol. Sci. 2024, 25, 370.
Julovi, S.M.; McKelvey, K.; Minhas, N.; Chan, Y.-K.A.; Xue, M.; Jackson, C.J. Involvement of PAR-2 in the Induction of Cell-Specific Matrix Metalloproteinase-2 by Activated Protein C in Cutaneous Wound Healing. Int. J. Mol. Sci.2024, 25, 370.
Julovi, S.M.; McKelvey, K.; Minhas, N.; Chan, Y.-K.A.; Xue, M.; Jackson, C.J. Involvement of PAR-2 in the Induction of Cell-Specific Matrix Metalloproteinase-2 by Activated Protein C in Cutaneous Wound Healing. Int. J. Mol. Sci. 2024, 25, 370.
Abstract
Background: We previously reported that human keratinocytes express protease-activated receptor (PAR)-2 and play an important role in activated protein C (APC)-induced cutaneous wound healing. This study investigated the involvement of PAR-2 in the production of gelatinolytic matrix metalloproteinases (MMP)-2 and -9 by APC during cutaneous wound healing. Methods: Full-thickness excisional wounds were made on the dorsum of male C57BL/6 mice. Wounds were treated with APC on days 1, 2, and 3 post-wounding. Cultured neonatal foreskin keratinocytes were treated with APC with or without intact PAR-2 signalling to examine the effects on MMP-2 and MMP-9 production. Murine dermal fibroblasts from PAR2 knock-out (KO) mice were also assessed. MMP-2 and -9 were measured by gelatin zymography, fluorometric assay, and immunohistochemistry. Results: APC accelerated wound healing in WT mice, but had negligible effect in PAR-2 KO mice. APC stimulated murine cutaneous wound healing was associated with differential 0temporal production of MMP-2 and MMP-9, with the latter peaking on Day 1 and the former on Day 6. In-hibition of PAR-2 in human keratinocytes reduced APC-induced MMP-2 activity 25~50, but had little effect on MMP-9. Similarly, APC-induced MMP-2 activation was reduced by 40% in cultured dermal fibroblasts derived from PAR-2 KO mice. Conclusion: This study shows for the first time that PAR-2 is essential for APC-induced MMP-2 production. Considering the important role of MMP-2 in wound healing, this work helps explain the underlying mechanisms of action of APC to promote wound healing through PAR2.
Keywords
Activated protein C; cutaneous wound healing; murine; matrix metalloproteinase-2, 9; and protease activated receptor-2
Subject
Medicine and Pharmacology, Dermatology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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