Impact of Sleep and Circadian Rhythm Disruption on Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Implications

Abstract

Background and Aim: Pulmonary arterial hypertension (PAH) is a progressive and deadly cardiopulmonary disease characterized by remodeling of pulmonary vessels and right ventricular dysfunction. Despite available treatments, the death rate remains high among patients. Emerging clinical data show a high prevalence of poor sleep quality in patients with PAH. However, it is still unclear whether or how sleep disruption contributes to PAH progression. Additionally, the role of the molecular clock in various diseases is well documented; however, how this clock affects pulmonary artery smooth muscle cell (PASMC) function and PAH remains largely underexplored. Methods: We used two models of sleep disruption (sleep fragmentation and chronic jet lag), four mouse models of PAH, and conducted hemodynamic and histomorphometric analyses to determine the effect of sleep disturbance on PAH. Bulk RNA sequencing, immunostaining, and immunoblotting assays were employed to investigate signaling mechanisms. Electroencephalography and electromyography (EEG/EMG) telemetry were used to assess sleep architecture in PAH mouse models. We then used melatonin and clodronate interventions to examine the roles of sleep modulation and inflammation reduction in PAH. The clock genes BMAL1 and CLOCK (key drivers of the molecular clock) in PASMCs were defined by synchronizing cells from healthy donors and PAH patients, followed by time-point qPCR. Finally, we explored the role of the clock gene in PAH using smooth muscle cell (SMC)-specific Bmal1 knockout mice. Results: Our data showed that sleep disruption significantly aggravated PAH, characterized by increased right ventricular systolic pressure (RVSP), enhanced RV hypertrophy, and greater pulmonary vascular remodeling. RNA-seq and immunostaining analyses of lung tissues revealed that sleep disruption caused substantial enrichment of inflammatory pathways, macrophage accumulation, and elevated levels of inflammatory cytokines. Further in vitro studies indicated that inflammatory cytokines markedly activated the IL6/STAT3/TGF-β/SMAD2/3 pathway in PASMCs, a finding also observed in vivo. EEG/EMG measurements demonstrated that PAH causes sleep disruption in mice. The combination of sleep-promoting and anti-inflammatory therapies significantly reduced PAH. PASMCs from PAH patients exhibited disrupted oscillations of BMAL1 and CLOCK, and SMC-specific deletion of Bmal1 protected mice from PAH symptoms. Conclusion: This dissertation shows that PAH and sleep disruption form a self-reinforcing pathological cycle, where PAH causes sleep disruption, and disturbed sleep further worsens PAH and amplifies disease progression. Combining sleep-promoting and anti-inflammatory strategies attenuates PAH in preclinical models. Concurrently, the circadian molecular clock component BMAL1 is dysregulated in PASMCs, leading to PASMC hyperproliferation through the cell cycle checkpoint, and SMC-specific inhibition of BMAL1 offers a promising therapy for PAH.