Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and Patients with Chronic Obstructive Pulmonary Disease

DNA damage resulting from cigarette smoke-induced oxidative stress activates the DDR signaling pathway, controlled mainly by the ATM (ataxia-telangiectasia mutated) protein kinase. The link between miR-126 and DDR signaling in COPD is currently unknown. [...]we investigated whether miR-126 is reduced by cigarette smoke in vivo and in endothelial and lung epithelial cells from patients with COPD, as well as its link to DDR activation. [...]miR-126 levels in lung epithelial cells negatively correlated with smoking history assessed as pack-years (Spearman's r = -0.73; P < 0.01) and positively correlated with disease severity measured as FEV1% predicted (Spearman's r = 0.57; P < 0.05), suggesting miR-126 expression is downregulated with extended exposure to cigarette smoke and increased severity of lung disease. Using a combined in vivo and ex vivo approach, namely, mice exposed to cigarette smoke and endothelial and lung epithelial cells from patients with COPD, we show that exposure to cigarette smoke downregulates miR-126 expression. miR-126 is critical for endothelial function, and miR-126 supplementation has been proposed therapeutically in in vivo models of vascular injury and pulmonary hypertension (5, 6).