ArticleNature cardiovascular research2025
Excessive HIF-1α driven by phospholipid metabolism causes septic cardiomyopathy through cytopathic hypoxia.
Article in Nature cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Endogenous H₂S promotes HSPA8 sulfhydration to downregulate HIF1α and prevent ferroptosis in septic myocardial injury.Redox report : communications in free radical research · 2026Article
- Integrated Network Pharmacology and Cross-Species Analysis Suggest a Potential Role of AKT1/HIF1A Axis in Shuanghuanglian for Pneumonia-Myocarditis Comorbidity.Veterinary sciences · 2026Article
- HIF-1α mediated placental ischemic signaling in the development of early-onset preeclampsia.Redox biology · 2026Review
- Cytokine-mediated, organ-specific immune modulation and dysregulation of innate lymphocytes in sepsis.Seminars in immunopathology · 2026Review
- Multi-omics analysis identifies NFIL3 as a hypoxia-associated immune regulator in septic cardiomyopathy.Frontiers in immunology · 2026Article
- Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury.Frontiers in immunology · 2026Review
- The immunometabolic axis of sepsis-related myocardial injury: macrophage reprogramming as a central mechanism and therapeutic target.Frontiers in immunology · 2026Review
- Vitamin C is associated with improved outcomes in patients with sepsis-induced myocardial injury: insights from the MIMIC-IV database.BMC infectious diseases · 2025Article
- Linking phospholipid metabolism to septic cardiomyopathy via HIF-1α overactivation.Nature cardiovascular research · 2025Article
- FGF2 Attenuated Inflammation-Mediated Cardiac Damage: A Novel Mechanistic Insight into the AMPK-FUNDC1-Mitophagy.Research (Washington, D.C.) · 2025Article
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Authors and funding
19 authors.
Funding
Abstract
Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia.
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