The apolipoprotein A‐I mimetic peptide, D‐4F, restrains neointimal formation through heme oxygenase‐1 up‐regulation

Abstract

D‐4F, an apolipoprotein A‐I (apoA‐I) mimetic peptide, possesses distinctly anti‐atherogenic effects. However, the biological functions and mechanisms of D‐4F on the hyperplasia of vascular smooth muscle cells (VSMCs) remain unclear. This study aimed to determine its roles in the proliferation and migration of VSMCs. In vitro, D‐4F inhibited VSMC proliferation and migration induced by ox‐LDL in a dose‐dependent manner. D‐4F up‐regulated heme oxygenase‐1 (HO‐1) expression in VSMCs, and the PI3K/Akt/AMP‐activated protein kinase (AMPK) pathway was involved in these processes. HO‐1 down‐regulation with siRNA or inhibition with zinc protoporphyrin (Znpp) impaired the protective effects of D‐4F on the oxidative stress and the proliferation and migration of VSMCs. Moreover, down‐regulation of ATP‐binding cassette transporter A1 (ABCA1) abolished the activation of Akt and AMPK, the up‐regulation of HO‐1 and the anti‐oxidative effects of D‐4F. In vivo, D‐4F restrained neointimal formation and oxidative stress of carotid arteries in balloon‐injured Sprague Dawley rats. And inhibition of HO‐1 with Znpp decreased the inhibitory effects of D‐4F on neointimal formation and ROS production in arteries. In conclusion, D‐4F inhibited VSMC proliferation and migration in vitro and neointimal formation in vivo through HO‐1 up‐regulation, which provided a novel prophylactic and therapeutic strategy for anti‐restenosis of arteries.

Comparison of Mechanisms of Endothelial Cell Protections Between High-Density Lipoprotein and Apolipoprotein A-I Mimetic Peptide

“…Accumulating evidences indicated that D-4F protects endothelial cells against ox-LDL-induced injury by antagonizing the down-regulation of pigment epithelium-derived factor (PEDF) (Ding et al, 2014). We also found that D-4F alleviates ox-LDL-induced oxidative stress and promotes endothelial repair through the eNOS/HO-1 pathway (Liu et al, 2017a; Liu et al, 2017b). Furthermore, D-4F accelerates vasodilatation and restrains atherosclerosis by both regulating phospholipid metabolites and decreasing plasma long-chain lysophosphatidylcholine (LysoPC) in LDL-R null mice (Ou et al, 2012).…”

“…Human umbilical vein endothelial cells (HUVECs) were isolated by collagenase-based digestion of umbilical veins from healthy donors (Liu et al, 2017a; Liu et al, 2017b). HUVECs were cultured in gelatin-coated polystyrene dishes with endothelial cell medium (ECM) supplemented with 5% fetal bovine serum (FBS) and endothelial cell growth supplement (ECGS) in an incubator with 5% CO 2 at 37°C (Liu et al, 2011).…”

“…In vitro ox-LDL was prepared via exposure of LDL to 5 μM CuSO 4 for 24 h at 37°C (Liu et al, 2017a; Liu et al, 2017b). The oxidation was terminated by adding EDTA-Na 2 to a final concentration of 1 mg/ml.…”

“…Then, ox-LDL was dialyzed against PBS for 48 h to remove EDTA-Na2 and sterilized again. The oxidation of LDL was tested by measuring thiobarbituric acid-reactive substances (TBARSs) (Liu et al, 2017a; Liu et al, 2017b).…”

Commentary: The apolipoprotein A-I mimetic peptide, D-4F, restrains neointimal formation through heme oxygenase-1 up-regulation

“…We read with great interest the work of Liu et al ( 2017b ) showing that D-4F inhibited vascular smooth muscle cells (VSMC) proliferation and migration in vitro and neointimal formation in vivo through heme oxygenase-1(HO-1) up-regulation. Authors' conclusions further demonstrate that HO-1 represents a druggable target for vascular injury prevention and that D-4F may be exploited as a safe and effective treatment to induce HO-1 into a clinical setting.…”