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

doi:10.1016/j.ejphar.2018.07.014

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 journal › Article › peer-review

14 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 language	English
Pages (from-to)	77-83
Number of pages	7
Journal	European Journal of Pharmacology
Volume	834
DOIs	https://doi.org/10.1016/j.ejphar.2018.07.014
State	Published - Sep 5 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier B.V.

Funding

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 .

Funders	Funder number
National Institutes of Health (NIH)
American Diabetes Association Inc	1-15-ACN-06
National Institute of General Medical Sciences	T32GM075762

Keywords

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

ASJC Scopus subject areas

Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejphar.2018.07.014

Cite this

Nguyen, T. T., Ding, D., Wolter, W. R., Champion, M. M., Hesek, D., Lee, M., Pérez, R. L., Schroeder, V. A., Suckow, M. A., Mobashery, S., & Chang, M. (2018). Expression of active matrix metalloproteinase-9 as a likely contributor to the clinical failure of aclerastide in treatment of diabetic foot ulcers. European Journal of Pharmacology, 834, 77-83. https://doi.org/10.1016/j.ejphar.2018.07.014

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

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.",

keywords = "Aclerastide, Angiotensin II, Diabetic foot ulcers, Matrix metalloproteinase-9, Reactive oxygen species",

author = "Nguyen, {Trung T.} and Derong Ding and Wolter, {William R.} and Champion, {Matthew M.} and Dusan Hesek and Mijoon Lee and P{\'e}rez, {Rocio L.} and Schroeder, {Valerie A.} and Suckow, {Mark A.} and Shahriar Mobashery and Mayland Chang",

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year = "2018",

month = sep,

day = "5",

doi = "10.1016/j.ejphar.2018.07.014",

language = "English",

volume = "834",

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Nguyen, TT, Ding, D, Wolter, WR, Champion, MM, Hesek, D, Lee, M, Pérez, RL, Schroeder, VA, Suckow, MA, Mobashery, S & Chang, M 2018, 'Expression of active matrix metalloproteinase-9 as a likely contributor to the clinical failure of aclerastide in treatment of diabetic foot ulcers', European Journal of Pharmacology, vol. 834, pp. 77-83. https://doi.org/10.1016/j.ejphar.2018.07.014

TY - JOUR

T1 - Expression of active matrix metalloproteinase-9 as a likely contributor to the clinical failure of aclerastide in treatment of diabetic foot ulcers

AU - Nguyen, Trung T.

AU - Ding, Derong

AU - Wolter, William R.

AU - Champion, Matthew M.

AU - Hesek, Dusan

AU - Lee, Mijoon

AU - Pérez, Rocio L.

AU - Schroeder, Valerie A.

AU - Suckow, Mark A.

AU - Mobashery, Shahriar

AU - Chang, Mayland

PY - 2018/9/5

Y1 - 2018/9/5

N2 - 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.

AB - 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.

KW - Aclerastide

KW - Angiotensin II

KW - Diabetic foot ulcers

KW - Matrix metalloproteinase-9

KW - Reactive oxygen species

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JO - European Journal of Pharmacology

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ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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