Endothelial microparticles are increased in congenital heart diseases and contribute to endothelial dysfunction

Ze-Bang Lin,Li Zhou,Hua-Ming Li,Yan-Sheng Wang,Jing Chen,Zhi-Ping Wang,Zhi-Jun Ou,Xi Zhang,Tian-Pu Cheng,Hao-Xiang Yuan,Hong-Bo Ci,Jing-Song Ou,Jun Xu,Yan Li,Dong-Hong Liu

doi:10.1186/s12967-016-1087-2

Abstract

BackgroundWe previously demonstrated that endothelial microparticles (EMPs) are increased in mitral valve diseases and impair valvular endothelial cell function. Perioperative systemic inflammation is an important risk factor and complication of cardiac surgery. In this study, we investigate whether EMPs increase in congenital heart diseases to promote inflammation and endothelial dysfunction.MethodsThe level of plasma EMPs in 20 patients with atrial septal defect (ASD), 23 patients with ventricular septal defect (VSD), and 30 healthy subjects were analyzed by flow cytometry. EMPs generated from human umbilical vascular endothelial cells (HUVECs) were injected into C57BL6 mice, or cultured with HUVECs without or with siRNAs targeting P38 MAPK. The expression and/or phosphorylation of endothelial nitric oxide synthase (eNOS), P38 MAPK, and caveolin-1 in mouse heart and/or in cultured HUVECs were determined. We evaluated generation of nitric oxide (NO) in mouse hearts, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured HUVECs and in mice.ResultsEMPs were significantly elevated in patients with ASD and VSD, especially in those with pulmonary hypertension when compared with controls. EMPs increased caveolin-1 expression and P38 MAPK phosphorylation and decreased eNOS phosphorylation and NO production in mouse hearts. EMPs stimulated P38 MAPK expression, TNF-α and IL-6 production, which were all inhibited by siRNAs targeting P38 MAPK in cultured HUVECs.ConclusionsEMPs were increased in adult patients with congenital heart diseases and may contribute to increased inflammation leading to endothelial dysfunction via P38 MAPK-dependent pathways. This novel data provides a potential therapeutic target to address important complications of surgery of congenial heart disease.

Highlights

We previously demonstrated that endothelial microparticles (EMPs) are increased in mitral valve dis‐ eases and impair valvular endothelial cell function
Recently, we demonstrated that circulating microparticles in patients with valvular heart disease impaired endothelium dependent vasodilation by uncoupling and inhibiting endothelial nitric oxide synthase [1]
We investigated, for the first time, whether EMPs increased in two common congenital heart diseases, atrial septal defect (ASD) and ventricular septal defect (VSD), and the impact and the mechanisms of action of EMPs to promote inflammation and subsequent endothelial dysfunction

Summary

Introduction

We previously demonstrated that endothelial microparticles (EMPs) are increased in mitral valve dis‐ eases and impair valvular endothelial cell function. We investigate whether EMPs increase in congenital heart diseases to promote inflammation and endothelial dysfunction. We previously showed that microparticles generated from endothelial cells induce acute lung injury, inhibit angiogenesis, and impair vasodilation [2, 3]. We demonstrated that the number of plasma endothelial microparticles (EMPs) is significantly higher in patients with mitral valve diseases leading to impairment of human mitral valve endothelial cell function [4]. We found that EMPs contain hundreds of proteins, some of which may impair vasodilation, induce lung injury and/or activate inflammation [5, 6]. Whether EMPs are consistently elevated in all congenital heart diseases remains unclear

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