Inhibition of PAI-1 Via PAI-039 improves dermal wound closure in diabetes
Diabetes, ISSN: 1939-327X, Vol: 64, Issue: 7, Page: 2593-2602
2015
- 18Citations
- 33Captures
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Metrics Details
- Citations18
- Citation Indexes18
- 18
- CrossRef13
- Captures33
- Readers33
- 33
Article Description
Diabetes impairs the ability to heal cutaneous wounds, leading to hospitalization, amputations, and death. Patients with diabetes experience elevated levels of plasminogen activator inhibitor 1 (PAI-1), regardless of their glycemic control. It has been demonstrated that PAI-1-deficient mice exhibit improved cutaneous wound healing, and that PAI-1 inhibition improves skeletal muscle repair in mice with type 1 diabetes mellitus, leading us to hypothesize that pharmacologically mediated reductions in PAI-1 using PAI-039 would normalize cutaneous wound healing in streptozotocin (STZ)-induced diabetic (STZ-diabetic) mice. To simulate the human condition of variations in wound care, wounds were aggravated or minimally handled postinjury. Following cutaneous injury, PAI-039 was orally administered twice daily for 10 days. Compared with nondiabetic mice, wounds in STZdiabetic mice healed more slowly. Wound site aggravation exacerbated this deficit. PAI-1 inhibition had no effect on dermal collagen levels or wound bed size. PAI- 039 treatment failed to improve angiogenesis in the wounds of STZ-diabetic mice and blunted angiogenesis in the wounds of nondiabetic mice. Importantly, PAI-039 treatment significantly improved epidermal cellular migration and wound re-epithelialization compared with vehicle-treated STZ-diabetic mice. These findings support the use of PAI-039 as a novel therapeutic agent to improve diabetic wound closure and demonstrate the primary mechanism of its action to be related to epidermal closure.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84957109471&origin=inward; http://dx.doi.org/10.2337/db14-1174; http://www.ncbi.nlm.nih.gov/pubmed/25754958; https://diabetesjournals.org/diabetes/article/64/7/2593/18835/Inhibition-of-PAI-1-Via-PAI-039-Improves-Dermal; https://dx.doi.org/10.2337/db14-1174; https://diabetes.diabetesjournals.org/content/64/7/2593
American Diabetes Association
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