P66Shc Mediates Mitochondrial Dysfunction Dependent on PKC Activation in Airway Epithelial Cells Induced by Cigarette Smoke.

Ming Zhang,Jingjing Tang,Qiuhong Zhang,Hu Shan,Yali Li,Jie Zhang,Xia Yang

doi:10.1155/2018/5837123

Abstract

Airway epithelial mitochondrial injury plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction. However, little is known about the effect of p66Shc on airway epithelial damage in the development of COPD. The aim of the present study is to investigate the roles of p66Shc and its upstream regulators in the mitochondrial injury of airway epithelial cells (Beas-2b) induced by cigarette smoke extract (CSE). Our present study revealed that CSE increased p66Shc expression and its mitochondrial translocation in concentration and time-dependent manners in airway epithelial cells. And p66Shc siRNA significantly attenuated mitochondrial dysfunction and cell injury when airway epithelial cells were stimulated with 7.5% CSE. The total and phosphorylated expression of PKCβ and PKCδ was significantly increased associated with mitochondrial dysfunction and cell injury when airway epithelial cells were exposed to 7.5% CSE. The pretreatments with pharmacological inhibitors of PKCβ and PKCδ could notably suppress p66Shc phosphorylation and its mitochondrial translocation and protect the mitochondria and cells against oxidative damage when airway epithelial cells were incubated with 7.5% CSE. These data suggest that a novel PKCβ/δ-p66Shc signaling pathway may be involved in the pathogenesis of COPD and other oxidative stress-associated pulmonary diseases and provide a potential therapeutic target for these diseases.

Highlights

Cigarette smoke is the major risk factor for the development of chronic obstructive pulmonary disease (COPD), which is characterized by persistent airflow limitation and pulmonary function decline [1]
Our present study has demonstrated that cigarette smoke extract (CSE) increased p66Shc expression and its mitochondrial translocation in concentration- and time-dependent manners and p66Shc Small Interfering RNA (siRNA) attenuated mitochondrial dysfunction and airway epithelial cell injury induced by CSE
Pretreatments with pharmacological inhibitors of PKCβ and PKCδ could significantly suppress p66Shc phosphorylation and its mitochondrial translocation and improve mitochondrial dysfunction when airway epithelial cells were exposed to CSE

Summary

Introduction

Cigarette smoke is the major risk factor for the development of chronic obstructive pulmonary disease (COPD), which is characterized by persistent airflow limitation and pulmonary function decline [1]. Inhaled cigarette smoke primarily encounters airway epithelium and results in airway inflammation and oxidative stress [2]. Some studies have demonstrated that cigarette smoke upregulates ROS levels in airway epithelial cells [4, 5] and systemic levels of oxidative stress are dramatically increased in smokers and COPD patients [6, 7]. Cigarette smoke-induced endogenous ROS in airway epithelial cells may play an important role in the pathogenesis of COPD. The mitochondrion is an important source of endogenous ROS which plays crucial roles in a variety of physiological and pathological circumstances [8]. It has been reported that cigarette smoke can lead to airway epithelial mitochondrial oxidative damage [10], but the underlying mechanism is still not fully understood

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