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|Title:||Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice||Authors:||Chong, Han Chung
Chan, Jeremy Soon Kiat
Goh, Chi Qin
Gounko, Natalia V.
Wong, Marcus Thien Chong
Choong, Cleo Swee Neo
Tan, Nguan Soon
|Keywords:||DRNTU::Science::Biological sciences::Molecular biology||Issue Date:||2014||Source:||Chong, H. C., Chan, J. S. K., Goh, C. Q., Gounko, N. V., Luo, B., Wang, X., et al. (2014). Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice. Molecular therapy, 22(9), 1593-1604.||Series/Report no.:||Molecular therapy||Abstract:||Impaired wound healing is a major source of morbidity in diabetic patients. Poor outcome has, in part, been related to increased inflammation, poor angiogenesis, and deficiencies in extracellular matrix components. Despite the enormous impact of these chronic wounds, effective therapies are lacking. Here, we showed that the topical application of recombinant matricellular protein angiopoietin-like 4 (ANGPTL4) accelerated wound reepithelialization in diabetic mice, in part, by improving angiogenesis. ANGPTL4 expression is markedly elevated upon normal wound injury. In contrast, ANGPTL4 expression remains low throughout the healing period in diabetic wounds. Exogenous ANGPTL4 modulated several regulatory networks involved in cell migration, angiogenesis, and inflammation, as evidenced by an altered gene expression signature. ANGPTL4 influenced the expression profile of endothelial-specific CD31 in diabetic wounds, returning its profile to that observed in wild-type wounds. We showed ANGPTL4-induced nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of inducible nitric oxide synthase (iNOS) expression in wound epithelia, thus revealing a hitherto unknown mechanism by which ANGPTL4 regulated angiogenesis via keratinocyte-to-endothelial-cell communication. These data show that the replacement of ANGPTL4 may be an effective adjunctive or new therapeutic avenue for treating poor healing wounds. The present finding also confirms that therapeutic angiogenesis remains an attractive treatment modality for diabetic wound healing.||URI:||https://hdl.handle.net/10356/106780
|DOI:||10.1038/mt.2014.102||Rights:||© 2014 The Author(s). This is the author created version of a work that has been peer reviewed and accepted for publication in Molecular Therapy, published by Nature Publishing Group on behalf of The Author(s). It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1038/mt.2014.102].||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||SBS Journal Articles|
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