title: The Abnormal Architecture of Healed Diabetic Ulcers Is the Result of FAK Degradation by Calpain 1.
abstract: Delayed wound healing is a major complication of diabetes occurring in approximately 15% of chronic diabetic patients. It not only significantly affects patients' quality of life but also poses a major economic burden to the health care system. Most efforts have been focused on accelerating wound reepithelialization and closure. However, even after healing the quality of healed tissue in diabetics is abnormal and recurrence is common (50-75%). Thus, understanding how diabetes alters the ultimate mechanical properties of healed wounds will be important to develop more effective approaches for this condition. Focal adhesion kinase is an intracellular protein kinase that plays critical roles in cell migration, focal adhesion formation, and is an important component of cellular mechanotransduction. We have found that focal adhesion kinase expression is downregulated under a high glucose condition both in vitro and in vivo. This is secondary to increased activity of calpain 1, the primary enzyme responsible for focal adhesion kinase degradation, which becomes induced in hyperglycemia. We demonstrate that selective inhibition of calpain 1 activation improves wound healing and normalizes the mechanical properties of diabetic skin, suggesting a new therapeutic approach to prevent diabetic wound recurrence.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Ma
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Sun Hyung
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Garg
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yoda R
authors.initials: YR
authors.lastname: Patta
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, USA. Electronic address: ggurtner@stanford.edu.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D017719:Diabetic Foot / Q000473:pathology*; D015536:Down-Regulation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000473:pathology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D051416:Focal Adhesion Protein-Tyrosine Kinases; D002154:Calpain; C484806:CAPN1 protein, human; D005947:Glucose