Pharmacological blockade of HDAC3 accelerates diabetic wound healing by regulating macrophage activation.

Autor: Karnam K; Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India., Sedmaki K; Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India., Sharma P; Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India., Mahale A; Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India., Ghosh B; Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India; Epigenetic Research Laboratory, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India., Kulkarni OP; Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, India. Electronic address: onkar@hyderabad.bits-pilani.ac.in.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2023 May 15; Vol. 321, pp. 121574. Date of Electronic Publication: 2023 Mar 15.
DOI: 10.1016/j.lfs.2023.121574
Abstrakt: Aims: Here, we report the effect of histone deacetylase 3 (HDAC3) inhibition associated with macrophage activation, IL-1β expression, angiogenesis and wound healing in diabetic mice.
Main Methods: To determine the expression of HDAC3 in diabetic mice wounds, hyperglycemia was induced in C57BL/6 mice with streptozotocin followed by induction of 6 mm wounds. To understand the effect of HDAC3 selective inhibitor, BG45, wound tissues were isolated for analysing M1/M2 markers expression, immune cells infiltration, angiogenesis and healing factors expression. CD11b + F4/80 + cells were sorted from the wound tissues and analysed for the expression of M1/M2 markers using RT-qPCR and flow cytometer. In cell based assays, HDAC3 expression was measured in macrophages stimulated with high glucose (HG) plus LPS. Macrophages treated with BG45 and HG + LPS were analysed for the expression of pro-IL-1β, mature IL-1β, oxidative stress and pro-inflammatory (M1) and anti-inflammatory (M2) factors.
Key Findings: HDAC3 was found to be upregulated in impaired diabetic mice wounds and in macrophages stimulated with HG + LPS. Topical application of BG45 loaded gel accelerated the wound healing in diabetic mice and was evident by improved expression of Collagen-1A, IL-10, TGF-β, and angiogenesis (CD31, VEGF). BG45 treatment decreased the expression of IL-1β, TNF-α, and IL-6 (M1 phenotype), reduced oxidative stress and promoted the expression of Arginase-1 and YM1/2 (M2 phenotype) in macrophages treated with HG + LPS. BG45 also improved the expression of CD11b + F4/80 + CD206 + cells in wound tissues and reduced expression of inflammatory markers.
Significance: HDAC3 is upregulated in diabetic mice wounds and HDAC3 selective inhibitor promotes the wound healing by regulating macrophage activation, angiogenesis and IL-1β.
Competing Interests: Declaration of competing interest Authors does not have any conflict of interest with anyone.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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