Effects of Chronic Intermittent Hypoxia on Cardiac Rhythm Transcriptomic Networks

Abstract

This chapter completes a series of four studies analyzing in a mouse model the genomic consequences of chronic obstructive sleep apnea during development from neonatal to puberty. Groups of two male and two female 1-day-old sibling mice each were subjected for 1, 2, or 4 weeks to normal atmospheric conditions or to chronic intermittent hypoxia, and the transcriptomes of their hearts profiled and compared. Our previous papers reported alterations of individual genes, gene ontology categories, translation regulators and responses to stress, and analyzed and quantified the topological changes of the heart rhythm determinant (HRD) genomic fabric, including the ranking of the HRD genes. HRD fabric was defined as the most stably expressed and interconnected gene web that might be responsible for the generation, maintenance, and modulation of the heart rhythm in each condition. Here, we introduce the new analysis of the network landscape to determine the ways by which Ca²⁺ and Wnt signaling pathways, translation initiation, and elongation factors, and SOX (i.e., sex-determining region Y-box) genes control the HRD fabric. We also analyze the changes in the networks by which connexin 43, the main protein that couples the cardiomyocytes by forming intercellular gap junction channels, modulates the HRD fabric during development under normoxic and hypoxic conditions. Remarkably, the amplitude of the transcriptomic alterations diminished from 1 to 4 weeks of hypoxia, indicating activation of certain acclimatization or accommodation mechanisms. In addition to regulation of expression level, our analyses revealed changes in the stability control and interlinking of functional gene networks as well as switch of dominant gene pairs. Thus, we found that Hif1a-Jup, Lmna-Pcdh7, and Eef1a2-Gnao1 are the most important pairs at 1, 2, and 4 weeks normoxia, respectively, while Jup-Slc25a20, Cdh16-Vezt, and Eif2ak4-Pcdh12 are the controlling pairs at 1, 2, and 4 weeks hypoxia, respectively. The analysis has shown that changes in expression control and coordination had substantial contributions to the overall transcriptomic differences. Moreover, with respect to magnitude, hypoxia transcriptomic effects are comparable to those associated to development. Altogether, these results indicate the profound remodeling of the HRD fabric and regulatory pathways in response to intermittent oxygen deprivation that may explain the cardiac arrhythmias experienced by teenagers suffering by chronic obstructive sleep apnea.