Adropin inhibits the progression of atherosclerosis in ApoE-/-/Enho-/- mice by regulating endothelial-to-mesenchymal transition

Teng Ying; LingZhen Wu; TingXiang Lan; ZhiXiong Wei; DanQing Hu; YiLang Ke; Qiong Jiang; Jun Fang

doi:10.1038/s41420-023-01697-3

Adropin inhibits the progression of atherosclerosis in ApoE^-/-/Enho^-/- mice by regulating endothelial-to-mesenchymal transition

Cell Death Discov. 2023 Oct 31;9(1):402. doi: 10.1038/s41420-023-01697-3.

Authors

Teng Ying^#^{1

2}, LingZhen Wu^#¹, TingXiang Lan^#^{1

3}, ZhiXiong Wei¹, DanQing Hu^{1

4}, YiLang Ke⁵, Qiong Jiang¹, Jun Fang⁶

Affiliations

¹ Department of Cardiology, Fujian Medical University Union Hospital; Fujian Cardiovascular Medical Center; Fujian Institute of Coronary Artery Disease; Fujian Cardiovascular Research Center, Fuzhou, PR China.
² Department of Cardiology, The First Affiliated Hospital of Jiangxi Medical College, Shangrao, PR China.
³ Department of Ultrasound, Longyan First Hospital Affiliated to Fujian Medical University, Longyan, PR China.
⁴ School of Health, Fujian Medical University, Fuzhou, PR China.
⁵ Department of Geriatrics, Fujian Medical University Union Hospital; Fujian Key Laboratory of Vascular Aging, Fujian Institute of Geriatrics, Fuzhou, PR China.
⁶ Department of Cardiology, Fujian Medical University Union Hospital; Fujian Cardiovascular Medical Center; Fujian Institute of Coronary Artery Disease; Fujian Cardiovascular Research Center, Fuzhou, PR China. ptfangjun@126.com.

^# Contributed equally.

Abstract

Adropin, a secreted protein, coded by energy homeostasis-associated gene (Enho), is recently reported to modulate atherogenesis, with endothelial-to-mesenchymal transition (EndMT) involved in the early process. We explored whether adropin may alleviate atherosclerosis by regulating EndMT. We found that an intraperitoneal injection of adropin [105 μg/(kg·d) for 13 weeks] inhibited the progression of high-fat diet (HFD)-induced aortic atherosclerosis in apolipoprotein E-deficient mice (ApoE^-/-) and those with double gene deletion (ApoE^-/-/Enho^-/-), as detected by Oil Red O and haematoxylin-eosin staining. In the aortas of ApoE^-/- mouse, adropin treatment ameliorated the decrease in the mRNA expression of endothelial cell markers (leukocyte differentiation antigen 31, CD31, and vascular endothelial cadherin, VE-cadherin), but increased that of EndMT markers (alpha smooth muscle actin, α-SMA, and fibroblasts specific protein-1). In vitro, an adropin treatment (30 ng/ml) arrested the hydrogen peroxide (H₂O₂)-induced EndMT in human umbilical vein endothelial cells (HUVECs), attenuated the morphological changes of HUVECs, reduced the number of immunofluorescence-positive α-SMA, increased the mRNA and protein expressions of CD31 and VE-cadherin, and decreased those of α-SMA. Furthermore, the adropin treatment decreased the mRNA and protein expressions of transforming growth factor (TGF)-β1 and TGF-β2, and suppressed the phosphorylation of downstream signal protein Smad2/3 in HUVECs. These mitigative effects of adropin on H₂O₂-induced EndMT were reversed by the transfection of TGF-β plasmid. The findings signify that adropin treatment may alleviate the atherosclerosis in ApoE^-/-/Enho^-/- mice by inhibiting EndMT via the TGF-β/Smad2/3 signaling pathway.