Atorvastatin regulates vascular smooth muscle cell phenotypic transformation by epigenetically modulating contractile proteins and mediating Akt/FOXO4 axis.

Atherosclerosis (AS) is a prevalent cardiovascular disease with severe morbidity and high mortality. Phenotypic regulation of vascular smooth muscle cells (VSMCs) from the contractile and quiescent phenotype to the synthetic type is a critical step for the vascular remodeling of AS. Atorvastatin, as a 3‑hydroxy‑3‑methyl‑glutaryl coenzyme A reductase inhibitor, presents an anti‑inflammatory effect to improve vascular endothelial functions. The aim of the present study was to examine the effect of atorvastatin on VSMCs phenotypic transformation and the underlying mechanism. The rat primary VSMCs were isolated and identified. The protein expression of contractile proteins, such as α‑SMA, SM‑MHC, and SM22α, was reduced by angiotensin II (AngII) and enhanced by atorvastatin, in which atorvastatin could reverse the effect of AngII in the VSMCs. The treatment of HDAC inhibitor trichostatin A was able to enhance AngII‑inhibited expression of α‑SMA and SM‑MHC. Atorvastatin regulated AngII‑associated VSMCs phenotypic transformation by epigenetically regulating contractile proteins. Moreover, atorvastatin modulated platelet‑derived growth factor‑BB (PDGF‑BB)‑induced VSMC phenotypic transformation by modulating the Akt/forkhead Box O4 (FOXO4) axis. Immunofluorescence analysis revealed that PDGF‑BB enhanced the accumulation of FOXO4 in the VSMCs, while the treatment of atorvastatin was able to attenuate this effect and the co‑treatment of Akt inhibitor LY294002 could further inhibit the phenotype. The treatment of PDGF‑BB enhanced the interaction of SRF with FOXO4 and myocardin in the VSMCs, in which the co‑treatment of atorvastatin and LY294002 could reverse the effect of PDGF‑BB in the system. Thus, atorvastatin regulates VSMCs phenotypic transformation by epigenetically modulating contractile proteins and mediating the Akt/FOXO4 axis. Findings of the present study provide new insights into the mechanism by which atorvastatin modulates VSMCs, providing valuable evidence for the application of atorvastatin in the treatment of AS.