Endogenous Tumor Necrosis Factor Protects the Adult Cardiac Myocyte against Ischemic-Induced Apoptosis in a Murine Model of Acute Myocardial Infarction

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 10; pp. 5456 - 5461
• Main Authors: Kurrelmeyer, Karla M., Michael, Lloyd H., Baumgarten, Georg, Taffet, George E., Peschon, Jacques J., Sivasubramanian, Natarajan, Entman, Mark L., Mann, Douglas L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 09.05.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Acute Disease; Animals; Antigens, CD - genetics; Antigens, CD - physiology; Apoptosis; Arteries; Biological Sciences; Coronary vessels; Coronary Vessels - physiology; Coronary Vessels - physiopathology; Disease Models, Animal; fas ligand; Heart; Heart attacks; Left coronary artery; Ligands; Ligation; Medical research; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Myocardial Infarction - genetics; Myocardial Infarction - physiopathology; Myocardial Infarction - prevention & control; Myocardial Ischemia - pathology; Myocardial Ischemia - physiopathology; Myocardium; Myocardium - pathology; Necrosis; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - physiology; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha - physiology; Tumor necrosis factors; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.070036297

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1/TNFR2-deficient mice (77.2% ± 15.3%) when compared with either wild-type mice (46.8% ± 19.4%) or TNFR1-deficient (47.9 ± 10.6%) or TNFR2-deficient (41.6% ± 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.