Expression of active matrix metalloproteinase-9 as a likely contributor to the clinical failure of aclerastide in treatment of diabetic foot ulcers

Trung T. Nguyen, Derong Ding, William R. Wolter, Matthew M. Champion, Dusan Hesek, Mijoon Lee, Rocio L. Pérez, Valerie A. Schroeder, Mark A. Suckow, Shahriar Mobashery, Mayland Chang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Chronic wounds are a complication of diabetes. Treatment for diabetic foot ulcers is complex with little clinical recourse, resulting in 108,000 lower-limb amputations annually in the United States alone. Matrix metalloproteinases (MMPs) play important roles in the pathology and in the repair of chronic wounds. We previously identified active MMP-8 and MMP-9 in wounds of diabetic mice and determined that MMP-8 accelerates wound repair, while MMP-9 is the culprit for the diabetic wound being refractory to healing. Aclerastide, a peptide analog of angiotensin II, recently failed in phase III clinical trials for treatment of diabetic foot ulcers. We demonstrate herein that treatment of wounds of diabetic mice with aclerastide results in elevated levels of reactive oxygen species and of active MMP-9, which is likely an important contributor to the failure of aclerastide in clinical trials.

Original languageEnglish (US)
Pages (from-to)77-83
Number of pages7
JournalEuropean Journal of Pharmacology
Volume834
DOIs
StatePublished - Sep 5 2018

Bibliographical note

Funding Information:
This work was supported by the American Diabetes Association Pathway to Stop Diabetes (grant 1-15-ACN-06 ). TTN is a Ruth L. Kirschtein National Research Service Award Fellow of the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, supported by training grant T32 GM075762 from the National Institutes of Health .

Publisher Copyright:
© 2018 Elsevier B.V.

Keywords

  • Aclerastide
  • Angiotensin II
  • Diabetic foot ulcers
  • Matrix metalloproteinase-9
  • Reactive oxygen species

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