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

TNF alpha is a cytokine wit pleiotropic functions in many organs. In the heart increased TNF alpha levels are not: only associated with heart failure, but also, paradoxically, with protection from ischemic damage. To test whether the protective role of TNF alpha in the heart is concentration-dependent, we studied two mouse heart models with low (two- to threefold) over-expression of endogenous TNF alpha: mice deficient in a translational repressor of TNF alpha mRNA, TIA-1(-/-), and (nice over-expressing human TNF alpha. Hearts lacking TIA-1 were characterized for their endogenous TNF alpha over-expression during normal Langendorff perfusion. To define which TNF alpha 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 [Ca2+] to determine their contractile response and Ca2+ sensitivity. All hearts with low over-expression of TNF alpha, independent of human or murine origin, have improved contractile performance and increased Ca2+ sensitivity (by 0.2-0.26 pCa). Hearts lacking TNFR 1 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 TNF alpha 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 TNF alpha increase the Ca2+ sensitivity of the heart via a TNFR1-mediated mechanism.