Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes

Yu Jen Chen; Shou Cheng Wu; Hsiang Ching Wang; Tung Ho Wu; Shyng Shiou F. Yuan; Tsai Te Lu; Wen Feng Liaw; Yun Ming Wang

doi:10.1021/acs.molpharmaceut.9b00586

Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes

Yu Jen Chen, Shou Cheng Wu, Hsiang Ching Wang, Tung Ho Wu, Shyng Shiou F. Yuan, Tsai Te Lu, Wen Feng Liaw, Yun Ming Wang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe₂(μ-SCH₂CH₂OH)₂(NO)₄] (DNIC-1) with a sustainable NO-release reactivity (t_1/2 = 27.4 ± 0.5 h at 25 °C and 16.8 ± 1.8 h at 37 °C) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable ^δNO-release reactivity on the activation of angiogenesis and wound healing.

Original language	English
Pages (from-to)	4241-4251
Number of pages	11
Journal	Molecular Pharmaceutics
Volume	16
Issue number	10
DOIs	https://doi.org/10.1021/acs.molpharmaceut.9b00586
State	Published - Aug 2019

Keywords

angiogenesis
growth factors
nitric oxide
wound healing

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

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10.1021/acs.molpharmaceut.9b00586

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title = "Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes",

abstract = "In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) with a sustainable NO-release reactivity (t1/2 = 27.4 ± 0.5 h at 25 °C and 16.8 ± 1.8 h at 37 °C) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable δNO-release reactivity on the activation of angiogenesis and wound healing.",

keywords = "angiogenesis, growth factors, nitric oxide, wound healing",

author = "Chen, {Yu Jen} and Wu, {Shou Cheng} and Wang, {Hsiang Ching} and Wu, {Tung Ho} and Yuan, {Shyng Shiou F.} and Lu, {Tsai Te} and Liaw, {Wen Feng} and Wang, {Yun Ming}",

year = "2019",

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doi = "10.1021/acs.molpharmaceut.9b00586",

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AU - Chen, Yu Jen

AU - Wu, Shou Cheng

AU - Wang, Hsiang Ching

AU - Wu, Tung Ho

AU - Yuan, Shyng Shiou F.

AU - Lu, Tsai Te

AU - Liaw, Wen Feng

AU - Wang, Yun Ming

PY - 2019/8

Y1 - 2019/8

N2 - In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) with a sustainable NO-release reactivity (t1/2 = 27.4 ± 0.5 h at 25 °C and 16.8 ± 1.8 h at 37 °C) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable δNO-release reactivity on the activation of angiogenesis and wound healing.

AB - In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) with a sustainable NO-release reactivity (t1/2 = 27.4 ± 0.5 h at 25 °C and 16.8 ± 1.8 h at 37 °C) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable δNO-release reactivity on the activation of angiogenesis and wound healing.

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KW - growth factors

KW - nitric oxide

KW - wound healing

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Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes

Abstract

Keywords

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