Low over-expression of TNFα in the mouse heart increases contractile performance via TNFR1

✍ Scribed by Ilka Pinz; Stephen D. Wax; Paul Anderson; Joanne S. Ingwall

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 321 KB
• Volume: 105
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.21798

✦ Synopsis

Abstract

TNFα is a cytokine wit pleiotropic functions in many organs. In the heart increased TNFα levels are not only associated with heart failure, but also, paradoxically, with protection from ischemic damage. To test whether the protective role of TNFα in the heart is concentration‐dependent, we studied two mouse heart models with low (two‐ to threefold) over‐expression of endogenous TNFα: mice deficient in a translational repressor of TNFα mRNA, TIA‐1^−/−^, and mice over‐expressing human TNFα. Hearts lacking TIA‐1 were characterized for their endogenous TNFα over‐expression during normal Langendorff perfusion. To define which TNFα receptor mediates cardiac protection, we also used mice lacking the TNFR1 receptor. Contractile function was assessed in isolated hearts perfused in the isovolumic Langendorff mode during and following global no‐flow ischemic stress and in response to varying extracellular [Ca^2+^] to determine their contractile response and Ca^2+^ sensitivity. All hearts with low over‐expression of TNFα, independent of human or murine origin, have improved contractile performance and increased Ca^2+^ sensitivity (by 0.2–0.26 pCa). Hearts lacking TNFR1 have contractile performance equal to wild type hearts. Recovery from ischemia was greater in TIA‐1^−/−^ and was diminished in TNFR1^−/−^. Better contractile function in TNFα over‐expressing hearts is not due to improved cardiac energetics assessed as [ATP] and glucose uptake or to differences in expression of SERCA2a or calmodulin. We suggest that low levels of TNFα increase the Ca^2+^ sensitivity of the heart via a TNFR1‐mediated mechanism. J. Cell. Biochem. 105: 99–107, 2008. © 2008 Wiley‐Liss, Inc.