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

Abstract

TNFalpha is a cytokine wit pleiotropic functions in many organs. In the heart increased TNFalpha levels are not only associated with heart failure, but also, paradoxically, with protection from ischemic damage. To test whether the protective role of TNFalpha in the heart is concentration-dependent, we studied two mouse heart models with low (two- to threefold) over-expression of endogenous TNFalpha: mice deficient in a translational repressor of TNFalpha mRNA, TIA-1(-/-), and mice over-expressing human TNFalpha. Hearts lacking TIA-1 were characterized for their endogenous TNFalpha over-expression during normal Langendorff perfusion. To define which TNFalpha 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 TNFalpha, 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 TNFalpha 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 TNFalpha increase the Ca(2+) sensitivity of the heart via a TNFR1-mediated mechanism.

• Authors: Ilka Pinz, Stephen D Wax, Paul Anderson, Joanne S Ingwall
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 105 Issue 1 Pg. 99-107 (Sep 01 2008) ISSN: 1097-4644 [Electronic] United States
• PMID: 18452158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Poly(A)-Binding Proteins
• RNA, Messenger
• Receptors, Tumor Necrosis Factor, Type I
• Tnfrsf1a protein, mouse
• Tumor Necrosis Factor-alpha
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Gene Expression Regulation
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle Contraction
• Myocardium (metabolism)
• Poly(A)-Binding Proteins (deficiency, genetics, metabolism)
• RNA, Messenger (genetics)
• Receptors, Tumor Necrosis Factor, Type I (deficiency, genetics, metabolism)
• Reperfusion Injury (genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)