TY - JOUR
T1 - Tumor necrosis factor-α does not modulate ischemia/reperfusion injury in naïve myocardium but is essential for the development of late preconditioning
AU - Dawn, Buddhadeb
AU - Guo, Yiru
AU - Rezazadeh, Arash
AU - Wang, Ou Li
AU - Stein, Adam B.
AU - Hunt, Greg
AU - Varma, Jai
AU - Xuan, Yu Ting
AU - Wu, Wen Jian
AU - Tan, Wei
AU - Zhu, Xiaoping
AU - Bolli, Roberto
N1 - Funding Information:
This study was supported in part by the National Institutes of Health grants R01 HL-43151, HL-55757, HL-68088, HL-70897 (R.B.), and HL-72410 (B.D.), American Heart Association Scientist Development Grant 0130146N (B.D.), American Heart Association Postdoctoral Fellowship Award 0325372B (A.B.S.), American Heart Association Ohio Valley Affiliate Grant 0265087B (Y.G.), the Medical Research Grant Program of the Jewish Hospital Foundation, Louisville, KY, and the Commonwealth of Kentucky Research Challenge Trust Fund. We gratefully acknowledge Sheron Lear for expert technical assistance and Marcia Joines and Carla Hilse for expert secretarial assistance.
PY - 2004/7
Y1 - 2004/7
N2 - The role of tumor necrosis factor (TNF)-α in myocardial ischemia/reperfusion injury remains controversial. We used homozygous TNF-α null mice (TNF-α-/-) to determine whether TNF-α modulates myocardial ischemia/reperfusion injury. Mice were subjected to a 30-min coronary occlusion followed by 24 h of reperfusion. When wild-type mice were preconditioned with six cycles of 4-min coronary occlusion/4-min reperfusion 24 h before the 30-min occlusion, infarct size was reduced from 58.6 ± 1.9% of the risk region to 19.3 ± 3.6%, indicating a late preconditioning (PC) effect. In non-preconditioned TNF-α-/- mice, infarct size was similar to that observed in wild-type mice (55.5 ± 3.7%). However, in TNF-α-/- mice preconditioned with six occlusion/reperfusion cycles 24 h earlier, infarct size was not reduced (55.2 ± 5.7%), indicating that the late PC protection against infarction was completely abolished. While minimal TNF-α immunoreactivity was detected in sham-operated hearts, extensive TNF-α expression was noted in the cytoplasm of cardiomyocytes in the ischemic/reperfused region 30 min after the PC ischemia. At 30 min after PC, wild-type mice exhibited increased DNA-binding activity of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) and nuclear translocation of p65, c-Jun and c-Fos; all of these changes were absent in TNF-α-/- mice. These data demonstrate that TNF-α does not modulate infarct size in the naïve (non-preconditioned) state but is essential for the development of the late phase of ischemic PC, possibly via the activation of NF-κB and AP-1 transcription factors.
AB - The role of tumor necrosis factor (TNF)-α in myocardial ischemia/reperfusion injury remains controversial. We used homozygous TNF-α null mice (TNF-α-/-) to determine whether TNF-α modulates myocardial ischemia/reperfusion injury. Mice were subjected to a 30-min coronary occlusion followed by 24 h of reperfusion. When wild-type mice were preconditioned with six cycles of 4-min coronary occlusion/4-min reperfusion 24 h before the 30-min occlusion, infarct size was reduced from 58.6 ± 1.9% of the risk region to 19.3 ± 3.6%, indicating a late preconditioning (PC) effect. In non-preconditioned TNF-α-/- mice, infarct size was similar to that observed in wild-type mice (55.5 ± 3.7%). However, in TNF-α-/- mice preconditioned with six occlusion/reperfusion cycles 24 h earlier, infarct size was not reduced (55.2 ± 5.7%), indicating that the late PC protection against infarction was completely abolished. While minimal TNF-α immunoreactivity was detected in sham-operated hearts, extensive TNF-α expression was noted in the cytoplasm of cardiomyocytes in the ischemic/reperfused region 30 min after the PC ischemia. At 30 min after PC, wild-type mice exhibited increased DNA-binding activity of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) and nuclear translocation of p65, c-Jun and c-Fos; all of these changes were absent in TNF-α-/- mice. These data demonstrate that TNF-α does not modulate infarct size in the naïve (non-preconditioned) state but is essential for the development of the late phase of ischemic PC, possibly via the activation of NF-κB and AP-1 transcription factors.
KW - Activator protein-1
KW - Late preconditioning
KW - Myocardial infarction
KW - Nuclear factor-kappa B
KW - Tumor necrosis factor-α
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U2 - 10.1016/j.yjmcc.2004.03.012
DO - 10.1016/j.yjmcc.2004.03.012
M3 - Article
C2 - 15242735
AN - SCOPUS:3142617357
VL - 37
SP - 51
EP - 61
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 1
ER -