Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-α-mediated cardiac inflammatory responses.
Inflammation contributes significantly to cardiac dysfunction. Although the initial phase of inflammation is essential for repair and healing, excessive proinflammatory cytokines are detrimental to the heart. We found that adenine nucleotide translocator isoform-1 (ANT1) protein levels were significantly decreased in the inflamed heart of C57BL/6 mice following cecal ligation and puncture. To understand the molecular mechanisms involved, we performed small-interfering RNA-mediated knockdown of ANT1 and studied tumor necrosis factor-α (TNFα)-induced inflammatory responses in myocardium-derived H9c2 cells and cardiomyocytes. ANT1 knockdown significantly increased swollen mitochondria and mitochondrial reactive oxygen species, concomitant with increased TNFα-induced NF-κB reporter gene activity and interleukin-6 and TNFα expression. A mitochondrial-targeted antioxidant mito-TEMPO attenuated TNFα-induced mitochondrial reactive oxygen species, NF-κB reporter gene activity, and cytokine expression in ANT1 knockdown cells. Interestingly, TNFα or lipopolysaccharide (LPS) treatment significantly decreased ANT1 protein levels, suggesting a feed-forward regulation of proinflammatory cytokine expression activated by ANT1 downregulation. These data suggest that ANT1 downregulation contributes to cardiac inflammation post-cecal ligation and puncture. Preventing ANT1 downregulation could provide a novel molecular target to temper cardiac inflammation.
Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
Shi
S
Pan
Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
Nadan
N
Wang
Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
Sara
S
Bisetto
Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
Bing
B
Yi
Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania shey-shing.sheu@jefferson.edu.
Shey-Shing
SS
Sheu
D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D017930:Genes, Reporter; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008933:Mitochondrial Swelling; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D033741:Adenine Nucleotide Translocator 1; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse
adenine nucleotide translocator; cytokine; inflammation; sepsis