Adenosine Reduces Cardiac TNF-α Production and Human Myocardial Injury Following Ischemia-Reperfusion

Abstract

Myocardial tumor necrosis factor-α (TNF-α) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury (I/R), sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages and cardiomyocytes themselves produce TNF-α. In this regard, adenosine (ADO) has been reported to reduce macrophage TNF-α production. Our purposes were to determine whether (1) I/R induces rat myocardial TNF-α production; (2) ADO decreases ischemia-induced rat myocardial TNF-α production; (3) ADO functionally protects human myocardium against I/R; and (4) TNF-α-binding protein (TNFBP; p55) confers similar protection when substituted for ADO pretreatment. To study this, human atrial trabeculae were obtained during cardiac surgery and suspended in organ baths, paced at 1 Hz, and force development was recorded during I/R (45/120 min) with or without ADO pretreatment (125 μM × 10 min), or TNFBP (1 μg/ml) during I/R. Isolated rat hearts were perfused using the Langendorff method undergoing I/R (20/40 min) with or without ADO pretreatment (125 μM × 2 min) and rat myocardial expression of TNF-α was assessed by ELISA. Results demonstrated that I/R increased rat myocardial TNF-α levels from 324 ± 36 to 902 ± 77 pg/g (P< 0.05; ANOVA and Bonferroni/Dunn) and decreased human myocardial developed force (DF) to 18 ± 2% of baseline (%BDF;P< 0.05). ADO pretreatment decreased ischemia-induced rat myocardial TNF-α production (356 ± 107 pg/g;P< 0.05) and increased postischemic DF of human myocardium to 39 ± 3% BDF (P< 0.05). Further substantiating the link between ischemia-induced TNF-α production and injury, TNFBP administration similarly improved post-I/R function of human myocardium (55 ± 5% BDF;P< 0.05 vs. I/R alone). We conclude that (1) I/R induces rat myocardial TNF-α production; (2) ADO pretreatment decreases I/R-induced rat myocardial TNF-α production; (3) ADO improves human myocardial function; (4) TNFBP confers similar protection; and (5) inhibition/ neutralization of TNF-α represents a novel strategy for protecting human myocardium against ischemia and reperfusion injury.