Cigarette smoke impairs pulmonary vascular function through nAChR activation

Abstract

Tobacco smoke is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major health concern worldwide. Despite current therapies alleviate symptoms; there remain some limitations in the efficacy of treatments to curb COPD and its cardiovascular morbidities, particularly pulmonary hypertension. Our previous studies demonstrate that cigarette smoke (CS) has direct effects on pulmonary vascular tone homeostasis and contribute to pulmonary arterial dysfunction. This is in part due to altered activity of the voltage-dependent K+ channel, and to an exacerbated oxidative stress promoting a switch in the sGCs redox state. However, further characterization of the molecular basis of CS-mediated PA dysfunction is needed for more effective targeted treatment and prevention. Our current studies explored these molecular pathways and specifically addressed their contribution to the cellular contractile apparatus within pulmonary arteries. Our results proved deleterious effects on the contractile machinery of pulmonary artery smooth muscle cells. Increased oxidative stress and calcium dysregulation resulting from the activation of acetylcholine receptors (nAChR) in the pulmonary artery led to the manifestation of these effects. This groundbreaking discovery unveiled, for the first time, the expression of these receptors in human pulmonary arteries. Furthermore, we proved that inhibitors directed at these receptors demonstrate efficacy in alleviating various harmful effects of smoking and safeguarding pulmonary artery function from damage. These discoveries hold significant clinical implications, as they suggest that treatment with nAChR-targeted inhibitors could constitute a viable therapeutic option for COPD-related pulmonary hypertension in patients who do not respond to conventional medication.