Alpha7 nicotinic acetylcholine receptor mediates chronic nicotine inhalation-induced cardiopulmonary dysfunction

Whitehead, Anna; Fried, Nicholas D.; Li, Zhen; Neelamegam, Kandasamy; Pearson, Charlotte S.; LaPenna, Kyle B.; Sharp, Thomas E; Lefer, David J.; Lazartigues, Eric; Gardner, Jason D.; Yue, Xinping

doi:10.1042/cs20220083

Cited by 6 publications

(3 citation statements)

References 48 publications

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“…Furthermore, the impact of nicotine exposure on the cardiovascular system is complex, as its direct effects differ according to cell type. Previous studies identified multiple nAChR alpha-subunits in rat arteries (47,48) and there is strong evidence that nicotine exerts deleterious effects on the vasculature through its interaction with nAChRs (49), being α7 nAChRs a key player in these processes (50). These results are in line with previous studies in which α7 nAChR is the transducer receptor for nicotinic signaling.…”

Section: Discussionsupporting

confidence: 89%

“…Additionally, previous studies have shown that nicotine induces reorganization of cytoskeletal structures in vascular SMC, including changes in α-actin, vimentin, and β-tubulin, and vascular dysfunction. These have been shown to be at least partially mediated by the α7 nAChR (51,52,53). On the other hand, α7 nAChR exhibits high permeability to calcium, enough to couple the activity of this receptor to intracellular calcium signaling pathways (54).…”

Section: Discussionmentioning

confidence: 99%

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Cigarette smoke impairs pulmonary vascular function through nAChR activation

Munar-Rubert,

Andreu-Martínez,

Rodríguez-Pérez

et al. 2024

Preprint

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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.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Cigarette smoke impairs pulmonary vascular function through nAChR activation

Munar-Rubert,

Andreu-Martínez,

Rodríguez-Pérez

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…These changes are abrogated by treatment with losartan, a specific AT 1 R antagonist ( 33 ). Nicotine-induced pulmonary hypertension, RV remodeling, and vascular dysfunction are ameliorated by α7 nicotinic cholinergic receptor knockout, and are absent in female mice ( 58 ). The pathogenesis of pulmonary hypertension induced by Sugen and hypoxia also involves α7 nicotinic cholinergic receptor-mediated cross-talk between cardiomyocytes and cardiac fibroblasts, leading to RV fibrosis ( 60 ).…”

Section: Methodsmentioning

confidence: 99%

Nicotine and novel tobacco products drive adverse cardiac remodeling and dysfunction in preclinical studies

Fried

Oakes²,

Whitehead³

et al. 2022

Front. Cardiovasc. Med.

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BackgroundThe heart undergoes structural and functional changes in response to injury and hemodynamic stress known as cardiac remodeling. Cardiac remodeling often decompensates causing dysfunction and heart failure (HF). Cardiac remodeling and dysfunction are significantly associated with cigarette smoking. Although cigarette smoking has declined, the roles of nicotine and novel tobacco products (including electronic cigarettes and heat-not-burn tobacco) in cardiac remodeling are unclear. In this perspective, we present evidence demonstrating maladaptive cardiac remodeling in nicotine-exposed mice undergoing hemodynamic stress with angiotensin (Ang)-II infusion and review preclinical literature linking nicotine and novel tobacco products with cardiac remodeling and dysfunction.MethodsAdult, male C57BL/6J mice were exposed to room air or chronic, inhaled nicotine for 8 weeks. A subset of mice was infused with Ang-II via subcutaneous osmotic mini-pumps during the final 4 weeks of exposure. Left ventricular structure and function were assessed with echocardiography.ResultsChronic, inhaled nicotine abrogated Ang-II-induced thickening of the left ventricular posterior wall, leading to reduced relative wall thickness. Ang-II infusion was associated with increased left ventricular mass index in both air- and nicotine-exposed mice.ConclusionsThese changes suggest a phenotypic shift from concentric hypertrophy to eccentric hypertrophy in nicotine-exposed, hemodynamically-stressed mice which could drive HF pathogenesis. These findings join a growing body of animal studies demonstrating cardiac remodeling and dysfunction following nicotine and electronic cigarette exposure. Further exploration is necessary; however, clinicians and researchers should not overlook these emerging products as potential risk factors in the pathogenesis of cardiac remodeling and associated diseases including HF.

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Alpha7 nicotinic acetylcholine receptor mediates chronic nicotine inhalation-induced cardiopulmonary dysfunction

Whitehead

Fried

et al. 2022

Clinical Science

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Cigarette smoking remains the leading modifiable risk factor for cardiopulmonary diseases; however, the effects of nicotine alone on cardiopulmonary function remain largely unknown. Previously, we have shown that chronic nicotine vapor inhalation in mice leads to the development of pulmonary hypertension (PH) with right ventricular (RV) remodeling. This study aims to further examine the cardiopulmonary effects of nicotine and the role of the α7 nicotinic acetylcholine receptor (α7-nAChR), which is widely expressed in the cardiovascular system. Wildtype (WT) and α7-nAChR knockout (α7-nAChR-/-) mice were exposed to room air (control) or nicotine vapor daily for 12 weeks. Consistent with our previous study, echocardiography and RV catheterization reveal that male WT mice developed increased RV systolic pressure with RV hypertrophy and dilatation following 12-week nicotine vapor exposure; in contrast, these changes were not observed in male α7-nAChR-/- mice. In addition, chronic nicotine inhalation failed to induce PH and RV remodeling in female mice regardless of genotype. The effects of nicotine on the vasculature were further examined in male mice. Our results show that chronic nicotine inhalation led to impaired acetylcholine-mediated vasodilatory response in both thoracic aortas and pulmonary arteries, and these effects were accompanied by altered endothelial nitric oxide synthase phosphorylation (enhanced inhibitory phosphorylation at threonine 495) and reduced plasma nitrite levels in WT but not α7-nAChR-/- mice. Finally, RNA sequencing revealed upregulation of multiple inflammatory pathways in thoracic aortas from WT but not α7-nAChR-/- mice. We conclude that the α7-nAChR mediates chronic nicotine inhalation-induced PH, RV remodeling and vascular dysfunction.

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Alpha7 nicotinic acetylcholine receptor mediates chronic nicotine inhalation-induced cardiopulmonary dysfunction

Cited by 6 publications

References 48 publications

Cigarette smoke impairs pulmonary vascular function through nAChR activation

Cigarette smoke impairs pulmonary vascular function through nAChR activation

Nicotine and novel tobacco products drive adverse cardiac remodeling and dysfunction in preclinical studies

Alpha7 nicotinic acetylcholine receptor mediates chronic nicotine inhalation-induced cardiopulmonary dysfunction

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