Cigarette Smoke Directly Promotes Pulmonary Arterial Remodeling and Kv7.4 Channel Dysfunction
Javier Sevilla‐Montero, David Labrousse-Arias, Cintia Fernández-Pérez, Laura Fernández Blanco, Bianca Barreira, Gema Mondéjar‐Parreño, Elvira Alfaro‐Arnedo, Icíar P. López, Sandra Pérez-Rial, Germán Peces‐Barba, José G. Pichel, Víctor I. Peinado, Ángel Cogolludo, Marı́a J. Calzada
Abstract
Abstract Rationale Cigarette smoke is considered the chief leading cause of chronic obstructive pulmonary disease (COPD). Its impact on the progressive deterioration of airways has been extensively studied, but its direct effects on the pulmonary vasculature are less known. Objectives To prove that pulmonary arterial remodeling in patients with COPD is not just a consequence of alveolar hypoxia but also due to the direct effects of cigarette smoke on the pulmonary vascular bed. Methods We have used different molecular and cell biology approaches, as well as traction force microscopy, wire myography, and patch-clamp techniques in human cells and freshly isolated pulmonary arteries. In addition, we relied on in vivo models and human samples to analyze the effects of cigarette smoke on pulmonary vascular tone alterations. Measurements and Main Results Cigarette smoke extract exposure directly promoted a hypertrophic, senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to an increase in the proliferative potential of nonexposed cells. Interestingly, these effects were significantly reversed by antioxidants. Furthermore, cigarette smoke extract affected cell contractility and dysregulated the expression and activity of the voltage-gated K+ channel Kv7.4. This contributed to the impairment of vasoconstriction and vasodilation responses. Most importantly, the levels of this channel were diminished in the lungs of smoke-exposed mice, smokers, and patients with COPD. Conclusions Cigarette smoke directly contributes to pulmonary arterial remodeling through increased cell senescence, as well as vascular tone alterations because of diminished levels and function in the Kv7.4 channel. Strategies targeting these pathways may lead to novel therapies for COPD.