Abstract 3882: Selective Inhibition of Mitochondrial ROS Attenuates TNF-alpha Expression in Cardiomyocytes and Preserves Myocardial Function in Endotoxemic Mice
Background: Tumour necrosis factor-alpha (TNF-α) plays an important role in cardiac pathophysiology. Lipopolysaccharide (LPS) induces cardiomyocyte TNF-α production, which contributes to myocardial depression during sepsis. The aim of this study was to investigate the contribution of mitochondrial reactive oxygen species (ROS) in cardiomyocyte TNF-α expression and myocardial dysfunction induced by LPS.
Methods and Results: In cultured mouse neonatal cardiomyocytes, over-expression of mitochondrial superoxide dismutase (SOD2) or incubation with mitochondria-targeted antioxidant peptide (SS31, 5 μM) significantly decreased ROS production and down-regulated TNF-α expression stimulated by LPS (5 μg/ml). Similar inhibitory effects were obtained by rotenone (2 μM) or over-expression of uncoupling protein 2, suggesting an important role of mitochondrial ROS from respiratory chain complex-I in TNF-α expression. Mitochondrial ROS production by LPS increased histone deacetylase-3 (HDAC3) activity via c-Src signalling, and blockade of HDAC3 or c-Src decreased TNF-α expression. These effects of mitochondrial ROS and HDAC3 on TNF-α expression were associated with the accumulation of NF-κB/p65 at the TNF-α promoter. In endotoxemic mice, cardiac specific over-expression of SOD2 or treatment with SS31 significantly reduced the accumulation of NF-κB/p65 at the TNF-α promoter and TNF-α production, and attenuated LPS-induced myocardial depression.
Conclusions: Mitochondrial ROS contributes to LPS-induced TNF-α expression through c-Src/HDAC3/NF-κB pathways. Blocking mitochondrial ROS attenuates myocardial depression in endotoxemia. Thus, targeting mitochondrial ROS may represent a potential therapeutic approach for myocardial dysfunction in sepsis.