Low shear stress induced HMGB1 translocation and release via PECAM-1/PARP-1 pathway to induce inflammation response.

Wei-Dong Qin,Hao Wang,Chen Li,Da-Wei Wu,Shao-Hua Mi,Fan Zhang,Mingxiang Zhang,Jian-Ning Zhang,Yang Ma,Gui-Xia Wang,Chiara Bolego

doi:10.1371/journal.pone.0120586

Abstract

Low shear stress (LSS) plays a critical role in the site predilection of atherosclerosis through activation of cellular mechanosensors, such as platelet endothelial cell adhesion molecule 1 (PECAM-1). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that regulates the expression of various inflammatory cytokines. The nuclear enzyme high mobility group box 1 (HMGB1) can induce inflammation response by binding to toll-like receptor 4 (TLR4). In the present study, we aimed to investigate the role and mechanism of HMGB1 in LSS induced inflammation in human umbilical vein endothelial cells (HUVECs). HUVECs were stimulated by undisturbed shear stress (USS, 1 Pa) and LSS (0.4 Pa) in our experiments. Gene expression was inhibited by small interfering RNA (siRNA). ICAM-1 expression was regulated by LSS in a time dependent manner. LSS can induce HMGB1 translocation from nucleus to cytoplasm and release. Compared with the USS, LSS could increase the protein expression of PECAM-1 and PARP-1 as well as the secretion of TNF-α and IL-1β. LSS induced the translocation of HMGB1 from nucleus to cytoplasm. Inhibition of HGMB1 reduced LSS-induced inflammatory response. Inhibition of PARP-1 suppressed inflammatory response through inhibiting TLR4 expression and HMGB1 translocation. PECAM-1 inhibition reduced LSS-induced ICAM-1 expression, TNF-α and IL-1β secretion, and monocytes adhesion. LSS can induce inflammatory response via PECAM-1/PARP-1/HMGB1 pathway. PARP-1 plays a fundamental role in HMGB1 translocation and TLR4 expression. Inhibition of PARP-1 may shed light on the treatment of HMGB1 involved inflammation during atherosclerosis.

Highlights

Atherosclerosis is a chronic inflammatory disease in the large and medium arteries
After human umbilical vein endothelial cells (HUVECs) were stimulated by Low shear stress (LSS) (0.4 Pa) for various times (0, 6, 12, 18, 24, 30, and 36 h), the protein and mRNA expression of intercellular adhesion molecule 1 (ICAM-1) was determined by western blot analysis and RT-PCR
The protein expression of ICAM-1 began to increase at 6 h, while it peaked at 12 h and decreased at 18 h (Fig. 1A and 1B)

Summary

Introduction

Atherosclerosis is a chronic inflammatory disease in the large and medium arteries. It is often associated with various risk factors, such as age, sex, and cigarette. Inflammatory cytokines play important roles in the development and progression of atherosclerosis.[1] Cellular adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), contribute to the inflammatory response and endothelial dysfunction.[2] They can mediate the margination, adhesion and transendothelial migration of circulating monocytes from the blood stream to the vessel wall.[3] They can recruit and activate monocytes to release matrix metalloproteinases (MMP), promote plaque rupture and initiate acute coronary syndromes

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