β-adrenergic receptor antagonists accelerate skin wound healing: Evidence for a catecholamine synthesis network in the epidermis

Christine E. Pullar, Amilcar Rizzo, Roslyn Rivkah Isseroff

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

The skin is our primary defense against noxious environmental agents. Upon injury, keratinocytes migrate directionally into the wound bed to initiate re-epithelialization, essential for wound repair and restoration of barrier integrity. Keratinocytes express a high level of β2-adrenergic receptors (β2-ARs) that appear to play a role in cutaneous homeostasis as aberrations in either keratinocyte β2-AR function or density are associated with various skin diseases. Here we report the novel finding that β-AR antagonists promote wound re-epithelialization in a "chronic" human skin wound-healing model. β-AR antagonists increase ERK phosphorylation, the rate of keratinocyte migration, electric field-directed migration, and ultimately accelerate human skin wound re-epithelialization. We demonstrate that keratinocytes express two key enzymes required for catecholamine (β-AR agonist) synthesis, tyrosine hydroxylase and phenylethanolamine-N-methyl transferase, both localized within keratinocyte cytoplasmic vesicles. Finally, we confirm the synthesis of epinephrine by measuring the endogenously synthesized catecholamine in keratinocyte extracts. Previously, we have demonstrated that β-AR agonists delay wound re-epithelialization. Here we report that the mechanism for the β-AR antagonist-mediated augmentation of wound repair is due to β2-AR blockade, preventing the binding of endogenously synthesized epinephrine. Our work describes an endogenous β-AR mediator network in the skin that can temporally regulate skin wound repair. Further investigation of this network will improve our understanding of both the skin repair process and the multiple modes of action of one of the most frequently prescribed class of drugs, hopefully resulting in a new treatment for chronic wounds.

Original languageEnglish (US)
Pages (from-to)21225-21235
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number30
DOIs
StatePublished - Jul 28 2006

ASJC Scopus subject areas

  • Biochemistry

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