FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses

Chen, Fanfeng; Zhan, Jiayu; Liu, Mi; Mamun, Abdullah Al; Huang, Shanshan; Tao, Yibing; Zhao, Jiaxin; Zhang, Yu; Xu, Yitie; He, Zili; Du, Shenghu; Lu, Wei; Li, Xiaokun; Chen, Zimiao; Xiao, Jian

doi:10.7150/ijbs.85692

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Int J Biol Sci 2023; 19(13):4340-4359. doi:10.7150/ijbs.85692 This issue Cite

Research Paper

FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses

Fanfeng Chen^1,2,3#, Jiayu Zhan^3#, Mi Liu^3#, Abdullah Al Mamun³, Shanshan Huang³, Yibing Tao³, Jiaxin Zhao³, Yu Zhang³, Yitie Xu³, Zili He³, Shenghu Du^1,2,3, Wei Lu², Xiaokun Li^1,2,3✉, Zimiao Chen^1✉, Jian Xiao^1,2,3✉

1. Department of Wound healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China.
2. The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China.
3. Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China.
^# These authors contributed equally to this work.

Citation:

Chen F, Zhan J, Liu M, Mamun AA, Huang S, Tao Y, Zhao J, Zhang Y, Xu Y, He Z, Du S, Lu W, Li X, Chen Z, Xiao J. FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses. Int J Biol Sci 2023; 19(13):4340-4359. doi:10.7150/ijbs.85692. https://www.ijbs.com/v19p4340.htm

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Abstract

An essential pathogenic element of acute limb ischemia/reperfusion (I/R) injury is microvascular dysfunction. The majority of studies indicates that fibroblast growth factor 2 (FGF2) exhibits protective properties in cases of acute I/R injury. Albeit its specific role in the context of acute limb I/R injury is yet unknown. An impressive post-reperfusion increase in FGF2 expression was seen in a mouse model of hind limb I/R, followed by a decline to baseline levels, suggesting a key role for FGF2 in limb survivability. FGF2 appeared to reduce I/R-induced hypoperfusion, tissue edema, skeletal muscle fiber injury, as well as microvascular endothelial cells (ECs) damage within the limb, according to assessments of limb vitality, Western blotting, and immunofluorescence results. The bioinformatics analysis of RNA-sequencing revealed that ferroptosis played a key role in FGF2-facilitated limb preservation. Pharmacological inhibition of NFE2L2 prevented ECs from being affected by FGF2's anti-oxidative and anti-ferroptosis activities. Additionally, silencing of kruppel-like factor 2 (KLF2) by interfering RNA eliminated the antioxidant and anti-ferroptosis effects of FGF2 on ECs. Further research revealed that the AMPK-HDAC5 signal pathway is the mechanism via which FGF2 regulates KLF2 activity. Data from luciferase assays demonstrated that overexpression of HDAC5 prevented KLF2 from becoming activated by FGF2. Collectively, FGF2 protects microvascular ECs from I/R injury by KLF2-mediated ferroptosis inhibition and antioxidant responses.

Keywords: FGF2, Ferroptosis, Oxidative stress, Microvascular damage, Limb ischemia/reperfusion

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APA

Chen, F., Zhan, J., Liu, M., Mamun, A.A., Huang, S., Tao, Y., Zhao, J., Zhang, Y., Xu, Y., He, Z., Du, S., Lu, W., Li, X., Chen, Z., Xiao, J. (2023). FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses. International Journal of Biological Sciences, 19(13), 4340-4359. https://doi.org/10.7150/ijbs.85692.

ACS

Chen, F.; Zhan, J.; Liu, M.; Mamun, A.A.; Huang, S.; Tao, Y.; Zhao, J.; Zhang, Y.; Xu, Y.; He, Z.; Du, S.; Lu, W.; Li, X.; Chen, Z.; Xiao, J. FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses. Int. J. Biol. Sci. 2023, 19 (13), 4340-4359. DOI: 10.7150/ijbs.85692.

NLM

CSE

Chen F, Zhan J, Liu M, Mamun AA, Huang S, Tao Y, Zhao J, Zhang Y, Xu Y, He Z, Du S, Lu W, Li X, Chen Z, Xiao J. 2023. FGF2 Alleviates Microvascular Ischemia-Reperfusion Injury by KLF2-mediated Ferroptosis Inhibition and Antioxidant Responses. Int J Biol Sci. 19(13):4340-4359.

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