MicroRNA-409-3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice.

Autor: Bestepe F; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Ghanem GF; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Fritsche CM; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Weston J; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Sahay S; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Mauro AK; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Sahu P; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Tas SM; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Ruemmele B; Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA., Persing S; Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA., Good ME; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Chatterjee A; Division of Plastic and Reconstructive Surgery, Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA., Huggins GS; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA., Salehi P; Division of Vascular Surgery, Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts, USA., Icli B; Department of Medicine, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Feb 15; Vol. 38 (3), pp. e23459.
DOI: 10.1096/fj.202302124RR
Abstrakt: Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type-2 diabetes (T2D). Expression of miR-409-3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non-wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR-409-3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA-Seq transcriptomic profiling revealed BTG2 as a target of miR-409-3p, where overexpression of miR-409-3p significantly decreased BTG2 mRNA and protein expression. A 3' untranslated region (3'-UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR-409-3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR-409-3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG-anti-proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial-specific and tamoxifen-inducible miR-409-3p knockout mice (MiR-409 IndECKO ) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR-409-3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.
(© 2024 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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