Abstract 59: A Protective Role Of Adenine Nucleotide Translocator 1 In The Inflammatory Response Following Myocardial Infarction
Background: Inflammation following myocardial infarction (MI) contributes significantly to the pathogenesis of heart failure. Although the initial stage of inflammatory response is necessary for the repair and healing of myocardium, excessive inflammation post MI causes adverse remodeling leading to heart failure. Recent studies suggest that mitochondrial dysfunction plays an important role in inflammation. However, the molecular target in cardiac mitochondria and the mechanisms of action remain unclear. We hypothesized that mitochondrial ADP/ATP carrier adenine nucleotide translocator isoform 1 (ANT1) is protective in post MI inflammation.
Methods and Results: MI was induced by permanent occlusion of left anterior descending artery in C57BL/6 mice. In the inflamed heart following MI, ANT1 protein levels were significantly decreased in the left ventricle (0.48±8.94%), indicating ANT1 down-regulation occurs in myocardial inflammation following MI. To delineate the mechanisms involved, we performed siRNA knockdown of ANT1 in myocardium-derived H9c2 cells and cardiomyocytes, and examined tumor necrosis factor alpha (TNFα)-induced pro-inflammatory response. Knocking down ANT1 significantly increased the expression of TNFα (~10-fold) and interleukin-6 (IL-6) (~3.6-fold) concomitant with increased reporter gene activity of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) (~61±1.22%) in response to TNFα. These effects were not due to mitochondria loss because no changes were detected for voltage-dependent anion channel, or cyclophilin D when ANT1 is knocked down. Confocal microscopy analysis indicated that ANT1 knockdown increased TNFα-induced donut/blob-shaped mitochondria (~4.9-fold). Interestingly, exogenous TNFα and lipopolysaccharide (LPS) in turn significantly decreased ANT1 protein levels (~37±13%; ~37±6%, respectively) suggesting a feed forward regulation of pro-inflammatory cytokine expression activated by ANT1 down-regulation.
Conclusion: These data suggest that cardiac inflammation is dependent on, in part, the function of ANT1. Preventing ANT1 down-regulation can be a novel molecular target to attenuate post MI inflammation and heart failure.
Author Disclosures: S. Pan: None N. Wang: None S. Sheu: None.
- © 2014 by American Heart Association, Inc.