Adenosine reduces cardiac TNF-alpha production and human myocardial injury following ischemia-reperfusion.
Myocardial tumor necrosis factor-alpha (TNF-alpha) 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-alpha. In this regard, adenosine (ADO) has been reported to reduce macrophage TNF-alpha production. Our purposes were to determine whether (1) I/R induces rat myocardial TNF-alpha production; (2) ADO decreases ischemia-induced rat myocardial TNF-alpha production; (3) ADO functionally protects human myocardium against I/R; and (4) TNF-alpha-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 microM x 10 min), or TNFBP (1 microgram/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 microM x 2 min) and rat myocardial expression of TNF-alpha was assessed by ELISA. Results demonstrated that I/R increased rat myocardial TNF-alpha 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-alpha 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-alpha 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-alpha production; (2) ADO pretreatment decreases I/R-induced rat myocardial TNF-alpha production; (3) ADO improves human myocardial function; (4) TNFBP confers similar protection; and (5) inhibition/neutralization of TNF-alpha represents a novel strategy for protecting human myocardium against ischemia and reperfusion injury.
Cain
B S
BS
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
Meldrum
D R
DR
Dinarello
C A
CA
Meng
X
X
Banerjee
A
A
Harken
A H
AH
D000241:Adenosine / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D006801:Humans; D007700:Kinetics; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D014409:Tumor Necrosis Factor-alpha; D000241:Adenosine