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

: 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.