Empagliflozin promotes skin flap survival by activating AMPK signaling pathway

Jialong Yang; Weijian Ye; Kaitao Wang; An Wang; Jiapeng Deng; Guodong Chen; Yizhen Cai; Zijie Li; Yiqi Chen; Dingsheng Lin

doi:10.1016/j.ejphar.2024.177207

Empagliflozin promotes skin flap survival by activating AMPK signaling pathway

Eur J Pharmacol. 2024 Dec 16:987:177207. doi: 10.1016/j.ejphar.2024.177207. Online ahead of print.

Authors

Affiliations

¹ Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China.
² Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, The First School of Clinical Medical, Wenzhou Medical University, China.
³ Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: lindingsheng@wmu.edu.cn.

PMID: 39694175
DOI: 10.1016/j.ejphar.2024.177207

Abstract

Flaps are widely used in surgical wound repair, yet distal necrosis poses a significant postoperative challenge, stemming from potential factors such as inadequate blood perfusion, inflammation, ischemia/reperfusion (I/R) injury, mitochondrial impairment, and subsequent ferroptosis. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has pharmacological activities that promote angiogenesis, mitophagy, and inhibit inflammation, I/R injury, and ferroptosis. However, it is unclear whether EMPA can enhance flap survival. Here, we established a modified McFarlane flap model and applied EMPA to demonstrate its mechanism of action. 24 rats were evenly divided into four groups: the control, low-dose EMPA (10 mg/kg), high-dose EMPA (30 mg/kg), and inhibitor groups. Molecular biology experiments demonstrated that EMPA promoted the expression of angiogenesis-related factors vascular endothelial growth factor (VEGF) and CD34. Additionally, it also increased superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) levels, thus suppressing oxidative stress. EMPA further alleviated inflammation by downregulating the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In vitro experiments showed that EMPA promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and reduce their reactive oxygen species (ROS) production. Further investigation demonstrated that EMPA improves flap prognosis by inducing the expression of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, further promoting mitophagy and inhibiting ferroptosis. These effects collectively contributed to the survival of the skin flap. Overall, our research elucidates the protective effects of EMPA on flap survival and its specific mechanisms, offering new insights into solving post-transplant flap necrosis.

Keywords: AMPK; Empagliflozin; Ferroptosis; Human umbilical vein endothelial cells; Mitophagy; Skin flap.