title: PKCδ inhibition normalizes the wound-healing capacity of diabetic human fibroblasts.
abstract: Abnormal fibroblast function underlies poor wound healing in patients with diabetes; however, the mechanisms that impair wound healing are poorly defined. Here, we evaluated fibroblasts from individuals who had type 1 diabetes (T1D) for 50 years or more (Medalists, n = 26) and from age-matched controls (n = 7). Compared with those from controls, Medalist fibroblasts demonstrated a reduced migration response to insulin, lower VEGF expression, and less phosphorylated AKT (p-AKT), but not p-ERK, activation. Medalist fibroblasts were also functionally less effective at wound closure in nude mice. Activation of the δ isoform of protein kinase C (PKCδ) was increased in postmortem fibroblasts from Medalists, fibroblasts from living T1D subjects, biopsies of active wounds of living T1D subjects, and granulation tissues from mice with streptozotocin-induced diabetes. Diabetes-induced PKCD mRNA expression was related to a 2-fold increase in the mRNA half-life. Pharmacologic inhibition and siRNA-mediated knockdown of PKCδ or expression of a dominant-negative isoform restored insulin signaling of p-AKT and VEGF expression in vitro and improved wound healing in vivo. Additionally, increasing PKCδ expression in control fibroblasts produced the same abnormalities as those seen in Medalist fibroblasts. Our results indicate that persistent PKCδ elevation in fibroblasts from diabetic patients inhibits insulin signaling and function to impair wound healing and suggest PKCδ inhibition as a potential therapy to improve wound healing in diabetic patients.
authors.forename: Mogher
authors.initials: M
authors.lastname: Khamaisi
authors.forename: Sayaka
authors.initials: S
authors.lastname: Katagiri
authors.forename: Hillary
authors.initials: H
authors.lastname: Keenan
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomou
authors.forename: Danielle
authors.initials: D
authors.lastname: Eschuk
authors.forename: Ana
authors.initials: A
authors.lastname: Tellechea
authors.forename: Aris
authors.initials: A
authors.lastname: Veves
authors.forename: Chenyu
authors.initials: C
authors.lastname: Huang
authors.forename: Dennis Paul
authors.initials: DP
authors.lastname: Orgill
authors.forename: Amy
authors.initials: A
authors.lastname: Wagers
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D017719:Diabetic Foot / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006207:Half-Life; D006801:Humans; D007328:Insulin / Q000502:physiology; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: D007328:Insulin; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta