Abstract
Nitric oxide (NO) donors have been shown to improve wound healing, but the mechanism is not well defined. Here we show that the novel NO donor nitrosyl-cobinamide (NO-Cbi) improved in vitro wound healing in several cell types, including an established line of lung epithelial cells and primary human lung fibroblasts. On a molar basis, NO-Cbi was more effective than two other NO donors, with the effective NO-Cbi concentration ranging from 3 to 10μM, depending on the cell type. Improved wound healing was secondary to increased cell migration and not cell proliferation. The wound healing effect of NO-Cbi was mediated by cGMP, mainly through cGMP-dependent protein kinase type I (PKGI), as determined using pharmacological inhibitors and activators, and siRNAs targeting PKG type I and II. Moreover, we found that Src and ERK were two downstream mediators of NO-Cbi's effect. We conclude that NO-Cbi is a potent inducer of cell migration and wound closure, acting via cGMP, PKG, Src, and extracellular signal regulated kinase (ERK).
Highlights
Nitric oxide (NO) and NO donors such as sydnonimines, diazeniumdiolates, S-nitrosothiols, and NO-containing nanoparticles have been shown to improve wound healing to varying degrees [1,2]
We found no effect of 8-CPT-cAMP, an EPAC and cAMPdependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) activator, when used under the same conditions as NO-Cbi (Fig. 4C)
Because Src and extracellular signal regulated kinase (ERK) are known to be involved in cell migration [31], and we previously demonstrated that Src and ERK are activated downstream of PKG [32], we assessed if they were involved in NO-Cbi enhancement of wound healing
Summary
Nitric oxide (NO) and NO donors such as sydnonimines, diazeniumdiolates, S-nitrosothiols, and NO-containing nanoparticles have been shown to improve wound healing to varying degrees [1,2]. NO is a gaseous signaling molecule that can have multiple molecular/biochemical effects including reaction with metalloenzymes [7], generation of reactive nitrogen species [8], formation of nitrosothiol groups [9], and nitration of protein tyrosine residues [10]. All of these reactions can have further secondary effects on a variety of signaling pathways that can translate to multiple and sometimes divergent physiologic effects. A key signaling pathway activated by NO, and where NO was first
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