An ApoA-I Mimic Peptide of 4F Promotes SDF-1α Expression in Endothelial Cells Through PI3K/Akt/ERK/HIF-1α Signaling Pathway.

Kaixuan Lv,Jielun Yu,Linlin Zhang,Guoshen Zhong,Nana Yang,Yanhua Shi,Lichun Zhang,Shangmin Chu,Mei Yang,Xia Wang,Lingyu Kong

doi:10.3389/fphar.2021.760908

Kaixuan Lv, Jielun Yu + Show 9 more

Open Access

https://doi.org/10.3389/fphar.2021.760908

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Abstract

Atherosclerosis (AS) seriously impairs the health of human beings and is manifested initially as endothelial cells (ECs) impairment and dysfunction in vascular intima, which can be alleviated through mobilization of endothelial progenitor cells (EPCs) induced by stromal-cell-derived factor-1α (SDF-1α). A strong inverse correlation between HDL and AS has been proposed. The aim of the present work is to investigate whether 4F, an apolipoprotein A-I (apoA-I, major component protein of HDL) mimic peptide, can upregulate SDF-1α in mice and human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. The protein levels of SDF-1α were measured by ELISA assay. Protein levels of HIF-1α, phosphorylated Akt (p-Akt), and phosphorylated ERK (p-ERK) were evaluated by Western blotting analysis. The results show that L-4F significantly upregulates protein levels of HIF-1α, Akt, and ERK, which can be inhibited by the PI3K inhibitor, LY294002, or ERK inhibitor, PD98059, respectively. Particularly, LY294002 can downregulate the levels of p-ERK, while PD98059 cannot suppress that of p-Akt. D-4F can upregulate the levels of HIF, p-Akt, and p-ERK in the abdominal aorta and inferior vena cava from mice. These results suggest that 4F promotes SDF-1α expression in ECs through PI3K/Akt/ERK/HIF-1α signaling pathway.

Highlights

As the leading cause of cardiovascular and cerebrovascular diseases, atherosclerosis (AS) seriously impairs the health of human beings (Torres et al, 2015)
The present study aims to investigate whether D-4F or L-4F promotes the expression of stromalcell-derived factor-1α (SDF-1α) in vivo or in vitro through the PI3K/Akt/HIF-1α or ERK/HIF-1α signaling pathways
It can be learned that D-4F at a concentration of 1 mg/kg/day for 9 days significantly upregulated the levels of SDF-1α in mice plasma compared with control group or the D-4F group before injection

Summary

Introduction

As the leading cause of cardiovascular and cerebrovascular diseases, atherosclerosis (AS) seriously impairs the health of human beings (Torres et al, 2015). It has been suggested that endothelial cells (ECs) impairment and dysfunction in vascular intima act as the initial event of AS onset (Schwartz et al, 2010). The restoration of impaired ECs contributes to the suppression of AS development. Endothelial progenitor cells (EPCs) can differentiate into ECs as the precursor cells of the latter. EPCs are involved in vascular integrity, function, and repair, along with angiogenesis (Asahara et al, 2011). Many studies have shown that EPCs can migrate to the damaged site in endothelium and mediate its regeneration, promote the neovascularization in ischemic lesions, and alleviate the progression of AS (Hill et al, 2003; Naito et al, 2012; Xu et al, 2014).

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