Cardiovascular drugs and therapy · 2026
PDK4-Associated Metabolic Reprogramming Contributes to Lactate Accumulation and Parthanatos-Related Changes in Septic Cardiomyocytes.
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Yang Shaodong, Yan Cairong, Xu Zhenwei, Huang Tianbao, Chen Jintu, Zhu Jingfa
Аннотация
BACKGROUND: Sepsis-related myocardial injury (SRMI) is characterized by metabolic reprogramming and cardiomyocyte death, but the relationship between these processes remains unclear. This study investigated the association between pyruvate dehydrogenase kinase 4 (PDK4)-related metabolic dysregulation and parthanatos-related changes in SRMI.
METHODS: SRMI was modeled using cecal ligation and perforation in mice and lipopolysaccharide-stimulated H9c2 cells. Myocardial injury, metabolic alterations, mitochondrial dysfunction, and parthanatos-related changes were assessed using RNA sequencing, histopathology, transmission electron microscopy, biochemical assays, Western blotting, RT-qPCR, immunofluorescence, and flow cytometry. PDK4 was silenced using siRNA in LPS-stimulated H9c2 cells for functional validation.
RESULTS: PDK4 was significantly upregulated in septic myocardium. This change was accompanied by increased PDH phosphorylation, pyruvate and lactate accumulation, ATP depletion, and mitochondrial ultrastructural damage. PAR accumulation increased, NAD⁺ levels decreased, and AIF/MIF nuclear translocation was enhanced, indicating prominent parthanatos-related changes. In LPS-stimulated H9c2 cells, PDK4 knockdown decreased the p-PDH/PDH ratio and lactate levels while increasing ATP levels. PDK4 silencing also reduced PAR accumulation, increased NAD⁺ levels, and decreased AIF/MIF nuclear translocation.
CONCLUSION: PDK4 contributes to metabolic dysregulation and parthanatos-related changes in septic cardiomyocytes. However, whether lactate directly mediates the relationship between PDK4 and parthanatos requires further rescue experiments.
METHODS: SRMI was modeled using cecal ligation and perforation in mice and lipopolysaccharide-stimulated H9c2 cells. Myocardial injury, metabolic alterations, mitochondrial dysfunction, and parthanatos-related changes were assessed using RNA sequencing, histopathology, transmission electron microscopy, biochemical assays, Western blotting, RT-qPCR, immunofluorescence, and flow cytometry. PDK4 was silenced using siRNA in LPS-stimulated H9c2 cells for functional validation.
RESULTS: PDK4 was significantly upregulated in septic myocardium. This change was accompanied by increased PDH phosphorylation, pyruvate and lactate accumulation, ATP depletion, and mitochondrial ultrastructural damage. PAR accumulation increased, NAD⁺ levels decreased, and AIF/MIF nuclear translocation was enhanced, indicating prominent parthanatos-related changes. In LPS-stimulated H9c2 cells, PDK4 knockdown decreased the p-PDH/PDH ratio and lactate levels while increasing ATP levels. PDK4 silencing also reduced PAR accumulation, increased NAD⁺ levels, and decreased AIF/MIF nuclear translocation.
CONCLUSION: PDK4 contributes to metabolic dysregulation and parthanatos-related changes in septic cardiomyocytes. However, whether lactate directly mediates the relationship between PDK4 and parthanatos requires further rescue experiments.