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Peer-reviewedCC BY 4.0PLOS One

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

  • Shuting Cheng1
  • Xin Zhuo2
  • Yuhan Deng3
  • Fan Hu4
  • Hanmin Liu5
  • Lihong Wan6
  • Zhou Jiang
6 affiliations
  1. 1Department of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, PR China
  2. 2NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, Sichuan, PR China
  3. 3West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR China
  4. 4Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR China
  5. 5Key Laboratory of Birth Defect and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, PR China
  6. 6Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, PR China
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{cheng2026sustained,
  title = {{Sustained hypoxia induces divergent response patterns in cardiac metabolic-immune adaptation and circadian rhythm regulation}},
  author = {Shuting Cheng and Xin Zhuo and Yuhan Deng and Fan Hu and Hanmin Liu and Lihong Wan and Zhou Jiang},
  journal = {PLOS One},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pone.0357966},
  url = {https://doi.org/10.1371/journal.pone.0357966},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Sustained hypoxia induces divergent response patterns in cardiac metabolic-immune adaptation and circadian rhythm regulation
AU  - Shuting Cheng
AU  - Xin Zhuo
AU  - Yuhan Deng
AU  - Fan Hu
AU  - Hanmin Liu
AU  - Lihong Wan
AU  - Zhou Jiang
PY  - 2026
DA  - 2026/09/11
JO  - PLOS One
DO  - 10.1371/journal.pone.0357966
UR  - https://doi.org/10.1371/journal.pone.0357966
AB  - 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.
SN  - 1932-6203
ER  -