In-depth proteomics and Phosphoproteomics reveal biomarkers and molecular pathways of chronic intermittent hypoxia in mice.

Abstract

Obstructive sleep apnea (OSA) syndrome is characterized by Chronic Intermittent Hypoxia (CIH). In this study, we employed Data-independent acquisition (DIA) Mass Spectrometry to conduct comprehensive proteomic and phosphoproteomic profiling of a murine model subjected to Chronic Intermittent Hypoxia (CIH), a model we had previously established. Utilizing three CIH and three normal control genioglossus samples, we gathered valuable insights into the molecular alterations associated with CIH. Our analyses identified a total of 4576 protein groups and 13,867 phosphosites. Differential analysis of the proteomic data highlighted a significant upregulation of Ras signaling (Egf, Ngf, and Fyb1) and calcium signaling (Tnn, Thbs4, and Ppp2r2d) in CIH samples, contrasting with a notable decrease in oxidative phosphorylation (Atp5mf, Atp5me, and Atp5mg). Additionally, we observed a substantial increase in the phosphorylation of PI3K-AKT signaling (Ptk2_Y861, Mapk3_T203, and Eif4b_S230) and HIF-1 signaling (Gapdh_S208, Eno3_T229, and Camk2b_T382) in CIH samples. These findings prompted a deeper investigation into the association of the characterized proteins and phosphoproteins with Obstructive Sleep Apnea (OSA). The comprehensive profiling revealed molecular signatures that may serve as valuable insights into the pathophysiology of chronic intermittent hypoxia and its link to obstructive sleep apnea. Our observations provide a foundation for future research endeavors, offering potential avenues for advancing our understanding and treatment strategies for these conditions. SIGNIFICANCE: The significance of this study lies in its comprehensive exploration of the molecular mechanisms underpinning Chronic Intermittent Hypoxia (CIH), a key feature of Obstructive Sleep Apnea (OSA). By employing Data-independent acquisition (DIA) Mass Spectrometry, this research provides an in-depth proteomic and phosphoproteomic analysis, uncovering critical signaling pathways and molecular alterations associated with CIH. The identification of significant changes in Ras and calcium signaling pathways, along with increased phosphorylation in PI3K-AKT and HIF-1 signaling, offers novel insights into the pathophysiological processes involved in CIH and OSA. These findings not only enhance our understanding of the molecular basis of OSA but also pave the way for the development of targeted therapeutic strategies, ultimately contributing to better management and treatment of OSA and related conditions.