Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation.

Sevilla-Montero, J.; Labrousse-Arias, D.; Fernandez-Perez, C.; Barreira, B.; Mondejar-Parreno, G.; Cogolludo, A.; Calzada, M. J.

doi:10.1101/555953

bioRxiv · 10.1101/555953

Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation.

Sevilla-Montero, J.·Labrousse-Arias, D.·Fernandez-Perez, C.·Barreira, B.·Mondejar-Parreno, G.·Cogolludo, A.·Calzada, M. J.

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Abstract

Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies nowadays. Exposure to cigarette smoking is considered the chief leading cause of COPD. Current drugs therapies improve patient quality of life, however they do not revert the progression of the disease. Therefore, a deeper study of the cellular and molecular mechanisms that underlie this pathology is required to be able to carry out targeted and effective treatments. Although the effects of cigarette smoke in the progressive deterioration of the airway have been extensively studied in COPD patients, its effects on pulmonary vasculature have been unexplored, due to the classic conception that vascular damage is a consequence of alveolar hypoxia and loss of capillary bed. In this paper, we aimed to study the effects of cigarette smoke extract (CSE) in regulating pulmonary arterial cells phenotypic modulation, in particular the effects in fibroblasts (hPAFib) and smooth muscle cells (hPASMC), and in murine pulmonary arteries. Our results demonstrated that CSE exposure had direct effects on hPAFib and hPASMC, promoting a senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to increase the proliferative potential of non-exposed cells. CSE also increased total ROS levels in hPAFib and hPASMC, and upregulated NADPH oxidase subunits NOX1 and p22phox. Most importantly, CSE affected cell contractility and dysregulated the expression and activity of voltage-gated K+ channel Kv7.4. This contributed to limit vascular responses impairing vasoconstriction and endothelium-dependent and independent relaxation.

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Sevilla-Montero, J., Labrousse-Arias, D., Fernandez-Perez, C., Barreira, B., Mondejar-Parreno, G., Cogolludo, A., Calzada, M. J.. 2019-02-21. Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation.. https://doi.org/10.1101/555953

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