Impact of β‐adrenergic receptors on UV‐induced skin damage, inflammation and photoprotective effect of carvedilol

Abstract

Our previous studies demonstrated that the β‐blocker drug carvedilol prevents ultraviolet (UV)‐induced skin cancer in mice. However, how carvedilol interferes with UV‐induced skin carcinogenesis is unknown. Since carvedilol is a β‐adrenergic receptor subtype nonselective antagonist, we hypothesized that carvedilol prevents skin cancer via binding to the β‐adrenergic receptors and inhibiting the adrenergic signaling. The present study has two aims: (1) to elucidate the role of the β‐adrenergic receptors (Adrb1 and 2) on UV‐induced skin damages and inflammation, which are the initial hallmarks driving skin carcinogenesis; and (2) to examine whether the preventive effects of carvedilol against UV‐induced detrimental events is dependent on the β‐adrenergic receptors. We utilized Adrb1/2 double knockout mice (Adrb1tm1BkkAdrb2tm1Bkk/J) on a mixed background (129S1/Sv*129X1/SvJ*C57BL/6J*DBA/2*FVB/N) and wild‐type mice on C57BL/6 background, exposed these mice to single or multiple doses of UV (300 mJ/cm2), and examined parameters relevant to skin damages and inflammation. Physical parameters measured were skin thickness and Sunburn Index. Molecular parameters were expression of COX2 and pro‐inflammatory cytokines as well as cyclobutane pyrimidine dimers (CPD). 10 uM Carvedilol dissolved in acetone was applied immediately after each UV irradiation. In the single dose UV study, in wild‐type mice, UV irradiation increased skin thickness by an average of 4.5% relative to control; in knock‐out mice, UV irradiation increased skin thickness by 3.5% relative to control. In wild‐type mice, UV increased the skin mRNA expression of IL‐1β and IL‐6 by 20 folds. However, interestingly, the increase of IL‐1β and IL‐6 was not observed in knock‐out mice. Similarly, in wild‐type mice, UV increased the skin protein expression of COX‐2 and total P53 both by 2 folds; however, the increase of COX‐2 and P53 was not observed in knock‐out mice. Slot blot analysis indicated UV irradiation greatly induced CPD formation in both wild‐type and knock‐out mice to the same degree. However, different from the results we obtained from SKH‐1 hairless mice, in both wild‐type and knock‐out mice, carvedilol showed modest effect on UV‐induced COX‐2, IL‐1β, IL‐6 and CPD formation. Since the knockout mice may be less sensitive to the UV, we repeated the experiment by exposing mice to four higher doses of UV (400 mJ/cm2) and mice received topical treatment of carvedilol or acetone immediately after each UV dose. In the multiple UV study, in both wild‐type and knock‐out mice, UV strongly increased skin thickness, Sunburn Index, expression of IL‐1β and IL‐6. Carvedilol treatment improved Sunburn Index in both wild‐type and knock‐out mice but did not show benefit for other parameters. Therefore, we conclude that the observed difference between wild‐type and knock‐out mice may be partly due to inter‐strain difference in sensitivity to UV‐induced skin inflammation. We cannot exclude the possibility that Adrb1/2 plays a role in UV‐induced skin events. Adrb1/2 may be critical factor for regulating UV‐induced apoptosis and inflammation. The effects of carvedilol on these events, although modest, did not show difference between the wild‐type and knock‐out mice, indicating β‐adrenergic receptor independent. Future studies should repeat these experiments using wild‐type and knock‐out mice on congenic background.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.