Influence of Epigenetic Histone Modifiers on PTEN/PI3K/Akt Signaling in Vascular Smooth Muscle Cells (VSMC)

Abstract

Activation and proliferation of VSMC are principal contributors to vascular remodeling and restenosis. Evidence indicates PTEN/PI3K/Akt signaling is important in the regulation of VSMC proliferation and contractility. Several epigenetic histone modifiers with HDAC inhibitory activity arrest VSMC proliferation and alter gene expression implicating involvement of epigenetic mechanism in vascular remodeling. Accordingly, butyrate and trichostatin A (TSA), well‐studied histone modifiers, arrest VSMC proliferation and alter cell cycle proteins expression. Since PTEN/PI3K/Akt signaling is important in the regulation of VSMC proliferation, here we investigate whether butyrate and TSA alter PTEN/PI3K/Akt signaling fittingly to cause arrest of VSMC proliferation. Proliferating VSMC treated with butyrate or TSA for different lengths of time were used to determine the activation state and expression levels of signaling proteins by western blotting. Analysis of phosphorylation states of PTEN, Akt and PDK1 reveals time‐dependent inhibition of Akt/PKB and PDK1 phosphorylation and stimulation of PTEN phosphorylation. Regarding downstream effectors, while phosphorylation of FOX3 is inhibited, no change in GSK3α/β phosphorylation state was observed in treated VSMC in addition to downregulation of NF‐KappaB. Taken together, it appears that by dampening several actions of Akt that are linked to its pro‐cell proliferation effects, butyrate and TSA cause arrest of VSMC proliferation SUPPORT: G12RR003045‐21 and C06RR012537 from NIH/NCRR