Sustained hypoxia induces divergent response patterns in cardiac metabolic-immune adaptation and circadian rhythm regulation

OBJECTIVE: Chronic hypoxia is a critical pathological factor in cardiovascular disease, yet the molecular mechanisms underlying cardiac adaptation to sustained hypoxic stress remain incompletely understood. METHODS: With 3 GEO datasets, we performed comparative transcriptomic analysis across three hypoxia paradigms (sustained, prenatal, and adult subacute hypoxia) using DESeq2, Pearson correlation analysis, and KEGG pathway enrichment. Permutation testing (n = 10,000) validated robustness. Disease enrichment analysis and cardiovascular drug target analysis were conducted using KEGG pathway-disease mappings and four drug-gene interaction databases. RESULTS: Sustained hypoxia induced 181 DEGs, prenatal hypoxia produced only 2, and adult subacute hypoxia yielded 67, with no overlap among groups. Eight circadian DEGs were identified in the sustained hypoxia group and 7 distinct circadian DEGs in the prenatal adult programmed heart group, with no overlap between the two sets. The circadian interactome showed dramatic remodeling: gene pairs decreased by 67.5% (160-52), with three adaptive patterns (enhanced synchronicity, interaction reversal, weakened synchronicity). ASS1 emerged as the predominant co-expression hub under hypoxia (88.5% vs 11.25% in normoxia), while Bmal1-Npas2 maintained stable correlation (r = 0.838 vs 0.829). Pathway analysis revealed divergent enrichment profiles: 55 KEGG pathways enriched in metabolic-immune system, only 3 pathways for circadian genes, with no overlap. Disease and drug target analyses further corroborated these divergent profiles. CONCLUSION: This study identifies ASS1 as a transcript-level co-expression hub within the circadian interaction network under hypoxia, demonstrates the divergent enrichment profiles of metabolic-immune versus circadian systems at the pathway, disease, and drug target levels, and offers potential therapeutic targets for chronic hypoxia-associated cardiovascular diseases.