TY - JOUR
T1 - β-Adrenergic Receptor Trafficking, Degradation, and Cell Surface Expression Are Altered in Dermal Fibroblasts from Hypertrophic Scars
AU - El Ayadi, Amina
AU - Prasai, Anesh
AU - Wang, Ye
AU - Herndon, David N.
AU - Finnerty, Celeste C.
N1 - Funding Information:
The authors thank Kasie Cole for editing and proofreading the manuscript. This project was supported by a Shriners Hospitals for Children fellowship to AE (84202) and by grants from Shriners Hospitals for Children (71001 to CCF and 80100, 71000, 71008, and 84080 to DNH), the National Institutes of Health (R01 GM112936 to CCF and R01 GM056687, P50 GM060338, and NIDILRR H133A120091 to DNH). The project was also conducted with the support of the University of Texas Medical Branch’s Institute for Translational Sciences, supported in part by a Clinical and Translational Science Award (UL1TR000071) from the National Center for Advancing Translational Sciences (NCATS). Studies to continue the elucidation of the effects of β-AR modulation on postburn wound healing and scarring are funded via R01 GM112936 from the National Institutes of Health/National Institute of General Medicine Sciences, “Effects of Chronic Catecholamines Exposure on Post-Burn Scarring.” The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. None of the study sponsors had any role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Publisher Copyright:
© 2018 The Authors
PY - 2018/7
Y1 - 2018/7
N2 - Burn trauma elevates catecholamines for up to 2 years and causes hypertrophic scarring. Propranolol, a nonspecific β1-, β2-adrenergic receptor (AR) inverse agonist, counters the hypermetabolic response to elevated catecholamines and may decrease hypertrophic scarring by an unknown mechanism. We investigated the effect of burn injury on β1-, β2-, and β3-AR expression, trafficking, and degradation in human dermal fibroblasts from hypertrophic scar [HSF], non-scar fibroblasts, and normal fibroblasts. We also investigated the modulation of these events by propranolol. Catecholamine-stimulated cAMP production was lower in HSFs and non-scar fibroblasts than in normal fibroblasts. β1- and β2-AR cell surface expression was lowest in HSFs, but propranolol increased cell surface expression of these receptors. Basal β2-AR ubiquitination was higher in HSFs than non-scar or normal fibroblasts, suggesting accelerated receptor degradation. β-AR degradation was mainly driven by lysosomal-specific polyubiquitination at Lys-63 in normal fibroblasts and HSFs, which was abrogated by propranolol. Propranolol also targeted β-AR to the proteasome in HSFs. Confocal imaging showed a lack of β2-AR–GFP trafficking to lysosomal compartments in catecholamine-stimulated HSFs. These data suggest that burn trauma alters the expression, trafficking, and degradation of β-ARs in dermal fibroblasts, which may then affect fibroblast responses to propranolol.
AB - Burn trauma elevates catecholamines for up to 2 years and causes hypertrophic scarring. Propranolol, a nonspecific β1-, β2-adrenergic receptor (AR) inverse agonist, counters the hypermetabolic response to elevated catecholamines and may decrease hypertrophic scarring by an unknown mechanism. We investigated the effect of burn injury on β1-, β2-, and β3-AR expression, trafficking, and degradation in human dermal fibroblasts from hypertrophic scar [HSF], non-scar fibroblasts, and normal fibroblasts. We also investigated the modulation of these events by propranolol. Catecholamine-stimulated cAMP production was lower in HSFs and non-scar fibroblasts than in normal fibroblasts. β1- and β2-AR cell surface expression was lowest in HSFs, but propranolol increased cell surface expression of these receptors. Basal β2-AR ubiquitination was higher in HSFs than non-scar or normal fibroblasts, suggesting accelerated receptor degradation. β-AR degradation was mainly driven by lysosomal-specific polyubiquitination at Lys-63 in normal fibroblasts and HSFs, which was abrogated by propranolol. Propranolol also targeted β-AR to the proteasome in HSFs. Confocal imaging showed a lack of β2-AR–GFP trafficking to lysosomal compartments in catecholamine-stimulated HSFs. These data suggest that burn trauma alters the expression, trafficking, and degradation of β-ARs in dermal fibroblasts, which may then affect fibroblast responses to propranolol.
UR - http://www.scopus.com/inward/record.url?scp=85046137253&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046137253&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2018.01.037
DO - 10.1016/j.jid.2018.01.037
M3 - Article
C2 - 29476776
AN - SCOPUS:85046137253
VL - 138
SP - 1645
EP - 1655
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 7
ER -