Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor-alpha-mediated cardiac inflammatory responses

Pan S, Wang N, Bisetto S, Yi B, Sheu SS. Downregulation of adenine nucleotide translocator 1 exacerbates tumor necrosis factor -mediated cardiac inflammatory responses. Am J Physiol Heart Circ Physiol 308: H39-H48, 2015. First published November 7, 2014; doi: 10.1152/ajpheart. 00330.2014.-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-alpha (TNF alpha)-induced inflammatory responses in myocardium-derived H9c2 cells and cardiomyocytes. ANT1 knockdown significantly increased swollen mitochondria and mitochondrial reactive oxygen species, concomitant with increased TNF -induced NF- B reporter gene activity and interleukin-6 and TNF expression. A mitochondrial-targeted antioxidant mito-TEMPO attenuated TNF -induced mitochondrial reactive oxygen species, NF- B reporter gene activity, and cytokine expression in ANT1 knockdown cells. Interestingly, TNF 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 postcecal ligation and puncture. Preventing ANT1 downregulation could provide a novel molecular target to temper cardiac inflammation.