Cortactin Modulates Lung Endothelial Apoptosis Induced by Cigarette Smoke

Abstract

Cigarette smoke (CS) is the primary cause of Chronic Obstructive Pulmonary Disease (COPD), and an important pathophysiologic event in COPD is CS-induced apoptosis in lung endothelial cells (EC). Cortactin (CTTN) is a cytoskeletal actin-binding regulatory protein with modulation by Src-mediated tyrosine phosphorylation. Based upon data demonstrating reduced CTTN mRNA levels in the lungs of smokers compared to non-smokers, we hypothesized a functional role for CTTN in CS-induced mitochondrial ROS generation and apoptosis in lung EC. Exposure of cultured human lung EC to CS condensate (CSC) led to the rearrangement of the actin cytoskeleton and increased CTTN tyrosine phosphorylation (within hours). Exposure to CS significantly increased EC mitochondrial ROS generation and EC apoptosis. The functional role of CTTN in these CSC-induced EC responses was explored using cortactin siRNA to reduce its expression, and by using a blocking peptide for the CTTN SH3 domain, which is critical to cytoskeletal interactions. CTTN siRNA or blockade of its SH3 domain resulted in significantly increased EC mitochondrial ROS and apoptosis and augmented CSC-induced effects. Exposure of lung EC to e-cigarette condensate demonstrated similar results, with CTTN siRNA or SH3 domain blocking peptide increasing lung EC apoptosis. These data demonstrate a novel role for CTTN in modulating lung EC apoptosis induced by CS or e-cigarettes potentially providing new insights into COPD pathogenesis.

LncRNA INPP5F ameliorates stress‐induced hypertension via the miR‐335/Cttn axis in rostral ventrolateral medulla

“…Neuronal apoptosis in RVLM contributes to sympathetic overactivity and increases the risk of hypertension 25,37 . Moreover, Cttn strongly affects apoptosis 38,39 . The PI3K‐AKT signal pathway has been proven to play an important role in apoptosis 40,41 .…”

“… 25 , 37 Moreover, Cttn strongly affects apoptosis. 38 , 39 The PI3K‐AKT signal pathway has been proven to play an important role in apoptosis. 40 , 41 Cttn is associated with the PI3K‐AKT pathway, 42 , 43 which participates in apoptosis.…”

“…The apoptosis of RVLM neurons promotes sympathetic outflow and accelerates the chances of hypertension 25,37 . Cortactin (CTTN), which is encoded by Cttn, exerts a key function in coupling membrane dynamics to cortical actin assembly 48 and has an anti‐apoptotic effect in various diseases 38,39,49 . The PI3K‐Akt signaling pathway modulates diverse cellular processes, including cell apoptosis 40,41,50 .…”

BMSCs mediates endothelial cell autophagy by upregulating miR‐155‐5p to alleviate ventilator‐induced lung injury

“…On the basis of the literature review, pulmonary endothelial cells could respond to multiple injurious stimuli. [ 49 ] Additionally, pulmonary endothelial cells were widely used in lung injury research. [ 50 ] Therefore, pulmonary endothelial cells were used to perform several in vitro experiments.…”

Mitochondrial network dynamics in pulmonary disease: Bridging the gap between inflammation, oxidative stress, and bioenergetics

“…Additionally, endothelial cells from emphysema patients exhibit higher levels of senescence markers than asymptomatic smokers and nonsmokers [ 165 ]. Moreover, CS induces apoptosis and mitochondrial ROS generation in pulmonary endothelial cells [ 167 ]. Despite both mitochondrial and endothelial cell dysfunction being implicated in COPD, very little is known about the role of mitochondria in endothelial cells during COPD, highlighting a significant knowledge gap that needs to be addressed.…”