Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase.
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).
University of California Irvine, Irvine, CA, United States. Electronic address: rspitler@uci.edu.
Ryan
R
Spitler
Raphaela
R
Schwappacher
Tao
T
Wu
Xiangduo
X
Kong
Kyoko
K
Yokomori
Renate B
RB
Pilz
Gerry R
GR
Boss
Michael W
MW
Berns
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003038:Cobamides / Q000737:chemistry / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*
D003038:Cobamides; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; C017142:cobinamide; D017869:Cyclic GMP-Dependent Protein Kinases
Cell migration; ERK; NO; NO-Cbi; Nitric oxide; PDE; PKG; SNP; Src; Wound healing; cGMP-dependent protein kinase; extracellular signal regulated kinase; nitrosyl-cobinamide; phosphodiesterase; sodium nitroprusside