Bidirectional Crosstalk Between Sleep and Pulmonary Arterial Hypertension

Abstract

BackgroundPulmonary Arterial Hypertension (PAH) is a devastating cardiopulmonary disease characterized by pulmonary vascular remodeling due to vascular cells dysfunction. Among other clinical signs, emerging data suggest poor sleep quality in patients with PAH; however, how poor sleep impacts hemodynamic burden, symptom severity, and pulmonary vascular remodeling during PAH progression remains unknown. MethodsWe used two models of sleep disturbances (sleep fragmentation and chronic jet lag) and different mouse models of PAH to determine the effects of poor sleep on PAH. We carried out timepoint quantitative RT-PCR analyses to define the clock gene oscillations in human pulmonary artery smooth muscle cells (PASMCs) isolated from non-PAH and PAH patients. Bulk RNA-sequencing analysis, immunostaining, and proliferation assays were used to explore the mechanisms by which poor sleep impacts PAH. Electroencephalogram and Electromyogram recordings (EEG/EMG) were used to determine whether PAH affects sleep in mice. ResultsPoor sleep exacerbated right ventricular dysfunction, pulmonary vascular remodeling, and PAH. RNA-seq and immunostaining analyses showed that poor sleep induces lung inflammation. Inflammation affected the pulmonary vascular molecular clock to drive PASMC hyperproliferation and increased migration. SMC-specific deletion of Bmal1 protected mice from RV dysfunction, pulmonary vascular remodeling, and PAH. EEG/EMG measurements demonstrated that PAH causes poor sleep quality in mice. Lastly, we showed that improving sleep via melatonin delivery and blunting inflammation with clodronate inhibited pulmonary vascular remodeling and PAH. ConclusionsOur study demonstrates that PAH causes poor sleep which in turn induces inflammation, increases PASMC proliferation, and exacerbates PAH. This suggests that the relationship between PAH and poor sleep is a self-amplifying cycle, and that a combination of hypnotic and anti-inflammatory drugs may give PAH patients better clinical outcomes. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIPAH causes poor sleep quality which in turn induces lung inflammation, PASMC proliferation, and exacerbated PAH. C_LIO_LIBmal1 rhythmicity is disrupted, and its expression is increased in lungs of patients with PAH. C_LIO_LISMC-specific deletion of Bmal1 protects from PAH. C_LIO_LIImproving sleep quality and blunting inflammation attenuates PAH. C_LI What Are the Clinical Implications?O_LIBmal1 represents a promising disease-modifying agent with potential for clinical translation in the treatment of PAH. C_LIO_LIA combination of hypnotic and anti-inflammatory drugs has therapeutic potential to treat PAH. C_LI