Knockdown of heme oxygenase-2 impairs corneal epithelial cell wound healing

Abstract

Heme oxygenase (HO) represents an intrinsic cytoprotective system based on its anti-oxidative and anti-inflammatory properties mediated via its products biliverdin/bilirubin and carbon monoxide (CO). We showed that deletion of HO-2 results in impaired corneal wound healing with associated chronic inflammatory complications. This study was undertaken to examine the role of HO activity and the contribution of HO-1 and HO-2 to corneal wound healing in an in vitro epithelial scratch injury model. A scratch wound model was established using human corneal epithelial (HCE) cells. These cells expressed both HO-1 and HO-2 proteins. Injury elicited a rapid and transient increase in HO-1 and HO activity; HO-2 expression was unchanged. Treatment with biliverdin or CORM-A1, a CO donor, accelerated wound closure by 10% at 24 h. Inhibition of HO activity impaired wound closure by more than 50%. However, addition of biliverdin or CORM-A1 reversed the effect of HO inhibition on wound healing. Moreover, knockdown of HO-2 expression, but not HO-1, significantly impaired wound healing. These results indicate that HO activity is required for corneal epithelial cell migration. Inhibition of HO activity impairs wound healing while amplification of its activity restores and accelerates healing. Importantly, HO-2, which is highly expressed in the corneal epithelium, appears to be critical for the wound healing process in the cornea. The mechanisms by which it contributes to cell migration in response to injury may reside in the cytoprotective properties of CO and biliverdin.

Functioning of an arteriovenous fistula requires heme oxygenase-2

“…HO-2, for example, is a survival factor in the endothelium as shown by the observations that HO-2 deficiency exacerbates apoptosis of endothelial cells incurred by either glutamate or TNF-␣ (3,34), whereas increased amounts of HO-2 protein reduce the lethal effects of hypoxia in endothelial cells (18). Deficiency of HO-2 promotes the appearance of an activated phenotype in aortic endothelial cells (4), and following the wounding of the corneal epithelium, deficiency of HO-2 enhances inflammatory responses and impairs reparative responses (5,17). Exacerbation of inflammatory responses induced by the deficiency of HO-2 may thus contribute to the decreased AVF flow and increased AVF failure observed in HO-2-deficient mice.…”

Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions

“…It is known that heme oxygenase promotes wound healing and migration of different cell types including epithelial cells migration [18,[22][23][24], and a recent study showed that Nrf2 knockout mice exhibited a delayed healing in the corneal epithelium [25]. Therefore, we examined whether DMF and carnosol could affect wound closure of ARPE cells using the scratch assay.…”

PhotoCORMs: CO release moves into the visible

“…6 Controlled amounts of carbon monoxide show a positive role in controlling cardiovascular and inflammatory impairment, in promoting wound healing, and bactericidal action. [7][8][9][10][11][12][13][14][15] Notably, the mode of action of CO in these beneficial roles is as-yet unresolved. However, that does not prevent exploitation of the positive behaviour of CO in medical applications.…”