Abstract 4015: Abnormal Regulation of Tumor Necrosis Factor-α Receptor-associated Factor 2 and Downstream P38 Mitogen-activated Protein Kinase by Glutathione S-transferase P1–1 in Dilated Cardiomyopathy Patients
Circulating levels of tumor necrosis factor-α(TNF-α) are an independent predictor of mortality in dilated cardiomyopathy (DCM) patients. Cellular TNF-α signaling occurs via TNF-α receptor-associated factor 2 (TRAF2)-dependent activation of the mitogen-activated protein kinase (MAPK) proinflammatory cascades. Glutathione S-transferase P1–1 (GSTP1–1), which is primarily involved in oxidative stress responses, has been implicated in the prevention of TNF-α-associated apoptosis through interaction with TRAF2 to suppress p38-MAPK activity. Whether this system could operate in DCM has not yet been identified. GSTP1 and TRAF2 mRNA and protein expression were examined in left ventricular biopsies of explanted DCM hearts in 15 patients and 10 controls using real-time RT-PCR and Western blotting, respectively. Active p38 protein expression was determined by Western blotting. Healthy human cardiac cells were treated with recombinant TNF-α separately and in combination with recombinant GSTP1 and cell lysates were subsequently examined for TRAF2 and active p38 protein expression. In DCM myocardial tissue, GSTP1 and TRAF2 mRNA and protein expression were upregulated compared to control hearts (p<0.01). Additionally, activated p38 was increased in DCM patients compared to controls (p<0.02). Treatment of cardiac cells with recombinant TNF-α resulted in cellular TRAF2 and upregulation of activated p38. Treatment with GSTP1 blocked TNFα-induced TRAF2 and activated p38 expression in vitro. These results suggest for the first time, that the GSTP1/TRAF2 system is involved in DCM. Moreover, experiments in vitro revealed that GSTP1 regulates the TNF-α/TRAF2-elicited p38 signaling cascade. Targeting TRAF2 might be beneficial in DCM treatment.