Open AccessIschemia Alone is Sufficient to Induce TNF-?? mRNA and Peptide in the Myocardium
Author(s) -
Brian D. Shames,
Hazel H Barton,
Leonid L. Reznikov,
Charles B. Cairns,
Anirban Banerjee,
Alden H. Harken,
Xianzhong Meng
Publication year - 2002
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/00024382-200202000-00006
Subject(s) - ischemia , tumor necrosis factor alpha , medicine , myocyte , endocrinology
Over-production of tumor necrosis factor-alpha (TNF-alpha) following myocardial ischemia-reperfusion contributes to cardiac dysfunction, and anti-TNF-alpha has therapeutic potential for myocardial protection in cardiac surgery with obligatory ischemia. It remains unclear, however, whether myocardial TNF-alpha production occurs during ischemia and whether cardiac myocytes constitute a source of myocardial TNF-alpha. Ischemia alone has been shown to activate myocardial NF-kappaB. We hypothesized that ischemia alone is sufficient to induce myocardial TNF-alpha gene expression and peptide synthesis. We examined TNF-alpha production and NF-kappaB activation in the isolated rat heart subjected to global normothermic ischemia. Myocardial ischemia resulted in rapid IkappaB-alpha degradation and NF-kappaB activation. Immunofluorescence staining detected NF-KB intranuclear translocation primarily in myocardial interstitial cells. Ischemia alone induced a time-dependent increase in myocardial TNF-alpha. TNF-alpha peptide increased to 20.3+/-3.0 pg/mg after 25 min of ischemia (P < 0.05 vs 8.9+/-2.0 pg/mg in perfusion control). TNF-alpha was also localized to myocardial interstitial cells. Increased TNF-alpha peptide level correlated with TNF-alpha mRNA expression. We conclude that ischemia alone induces TNF-a gene expression and peptide synthesis in the myocardium that are associated with NF-kappaB activation. Non-myocytes constitute the main source of myocardial TNF-alpha following ischemia. The results suggest that therapeutic strategies attempting to decrease myocardial TNF-alpha production need to be applied before or in the early phase of ischemia.