The Essential Role of Pin1 via NF-κB Signaling in Vascular Inflammation and Atherosclerosis in ApoE-/- Mice.

Ming Liu,Junbo Ge,Xue Yang,Yunzeng Zou,Hong Jiang,Ji Zhao,Peng Yu

doi:10.3390/ijms18030644

Abstract

Atherosclerosis, as a chronic inflammatory disease, is the major underlying cause of death worldwide. However, the mechanisms that underlie the inflammatory process are not completely understood. Prolyl-isomerase-1 (Pin1), as a unique peptidyl-prolyl isomerase, plays an important role in inflammation and endothelial dysfunction. Herein, we investigate whether Pin1 regulates vascular inflammation and atherosclerosis, and clarify its mechanisms in these processes. ApoE−/− mice were randomly given either juglone (0.3, 1 mg/kg, two times per week) or vehicle i.p. for 4 weeks. Compared with ApoE−/− mice, treatment by juglone resulted not only in markedly attenuated macrophage infiltration and atherosclerotic lesion area in a lipid-independent manner, but also in decreased expression of Pin1, vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and NF-κB activity in aorta. Then, EA.hy926 cells were pretreated with juglone (6 μmol/L), Pin1 siRNA, NF-κB inhibitor, or vehicle prior to exposure to ox-LDL (50 μg/mL). It was observed that treatment with juglone or Pin1 siRNA suppressed expression of VCAM-1 in oxLDL-incubated EA.hy926 cells and decreased THP-1 cell adhesion to oxLDL-stimulated endothelial cells through the NF-κB signal pathway. Our findings indicate that Pin1 plays a vital role on the development of vascular inflammation and atherosclerosis.

Highlights

Atherosclerosis, as a chronic inflammatory disease, is the major underlying cause of death worldwide
It has been reported that Pin1 plays a pivotal role in chronic inflammation diseases such as rheumatoid arthritis [5], asthma [6], and liver fibrosis [7]
Pin1 inhibition suppressed vascular inflammation and atherosclerosis as well as activation of NF-κB signaling in ApoE−/− mice; Second, Pin1 inhibition improved oxLDL-induced inflammatory response in endothelial cells; Third, Pin1 inhibition suppressed the activation of NF-κB and decreased endothelial cells activation induced by oxLDL, at least partly via NF-κB signaling

Summary

Introduction

Atherosclerosis, as a chronic inflammatory disease, is the major underlying cause of death worldwide. Endothelial dysfunction is a critical event in atherosclerosis, which recruits macrophages into intima and contributes to the initiation of atherosclerosis [1,2]. Elucidating the molecular mechanisms that underlie the inflammatory process in early atherosclerosis conduces to the development of novel intervention strategies for atherosclerosis. Prolyl-isomerase-1 (Pin1), as a unique peptidyl-prolyl isomerase, is an enzyme that regulates cellular functions through conformational changes of proteins [3]. It has been reported that Pin plays a pivotal role in chronic inflammation diseases such as rheumatoid arthritis [5], asthma [6], and liver fibrosis [7]. Recent data revealed that Pin1-dependent conformational changes reduced nitric oxide availability and induced endothelial dysfunction [8].

Methods

Discussion

Conclusion