p66Shc Mediates Mitochondrial Dysfunction Dependent on PKC Activation in Airway Epithelial Cells Induced by Cigarette Smoke

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.

The Antioxidant MitoQ Protects Against CSE-Induced Endothelial Barrier Injury and Inflammation by Inhibiting ROS and Autophagy in Human Umbilical Vein Endothelial Cells

“…Chronic obstructive pulmonary disease is a complex progressive disease characterized by chronic inflammation, irreversible airflow limitation and emphysema. Cigarette smoke is considered to be a major risk factor for the development of COPD 32, 33. However, the mechanism of pathogenesis is yet to be elucidated.…”

Sirtuin 3 Inhibits Airway Epithelial Mitochondrial Oxidative Stress in Cigarette Smoke-Induced COPD

“…Structural and functional changes of the mitochondria in the epithelium of COPD lungs are potentially the consequence of long-term exposure to cigarette smoke [ 27 ]. In a previous study, we demonstrated that CSE induced mitochondrial damage of airway epithelial cells, including MMP loss, mitochondrial ROS increase, and ATP decline [ 24 ]. In addition, mitophagy promotes cigarette smoke-induced mitochondria and airway epithelial cell damage [ 28 , 29 ].…”

“…Septwolves cigarettes were used to prepare CSE as described earlier [ 24 ]. Briefly, a total of 300 mL cigarette smoke was collected by a syringe apparatus and bubbled in 10 mL RPMI medium.…”

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“…132,160 Nanoparticles were also used to deliver siRNA of 66 kDa proto-oncogene Src homologouscollagen homologue (p66shc) which is involved in cartilage degeneration in OA and known to mediate oxidative stress-induced apoptosis. 161 By delivering p66shc-siRNAloaded Poly(lactide-co-glycolide) (PLGA) nanoparticles into the osteoarthritic knee joints, mitochondrial dysfunction-induced cartilage damage was significantly impaired suggesting them as an option for the treatment of OA. 122 In addition to being effective, nanoparticles should be highly cytocompatible, or capable to be easily eliminated, eg, by self-degradation to disappear, and not to accumulate and produce unwanted adverse effects.…”