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

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 [Ca2+] to determine their contractile response and Ca2+ sensitivity. All hearts with low over‐expression of TNFα, independent of human or murine origin, have improved contractile performance and increased Ca2+ 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 Ca2+ sensitivity of the heart via a TNFR1‐mediated mechanism. J. Cell. Biochem. 105: 99–107, 2008. © 2008 Wiley‐Liss, Inc.

[1]  R. Scott,et al.  Synthesis and use of caged sphingolipids. , 2000, Methods in enzymology.

[2]  J. Ingwall,et al.  Impaired cardiac energetics in mice lacking muscle-specific isoenzymes of creatine kinase. , 1998, Circulation research.

[3]  P. Vandenabeele,et al.  Tumor necrosis factor-alpha-induced activation of RhoA in airway smooth muscle cells: role in the Ca2+ sensitization of myosin light chain20 phosphorylation. , 2003, Molecular pharmacology.

[4]  L. Opie,et al.  Increased glycolysis during ischaemia mediates the protective effect of glucose and insulin in the isolated rat heart despite the presence of cardiodepressant exogenous substrates. , 2002, Cardiovascular journal of South Africa : official journal for Southern Africa Cardiac Society [and] South African Society of Cardiac Practitioners.

[5]  F. Eberli,et al.  ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate. , 2000, Circulation.

[6]  L. Opie,et al.  Identification of a novel role for sphingolipid signaling in TNF alpha and ischemic preconditioning mediated cardioprotection. , 2002, Journal of molecular and cellular cardiology.

[7]  N. Dhalla,et al.  Mechanism of cardioprotective action of TNF-alpha in the isolated rat heart. , 2002, Experimental and clinical cardiology.

[8]  D. MacEwan.  TNF receptor subtype signalling: differences and cellular consequences. , 2002, Cellular signalling.

[9]  P. Blackshear,et al.  Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor α, cyclooxygenase 2, and inflammatory arthritis , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. M. McFarlane,et al.  TNF-α receptors simultaneously activate Ca2+ mobilisation and stress kinases in cultured sensory neurones , 2002, Neuropharmacology.

[11]  Michael D. Schneider,et al.  TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. , 2007, The Journal of clinical investigation.

[12]  B. Lowell,et al.  Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. , 1999, The Journal of clinical investigation.

[13]  D. Mann,et al.  Soluble TNF binding proteins modulate the negative inotropic properties of TNF-alpha in vitro. , 1995, The American journal of physiology.

[14]  P. Anderson,et al.  TIA‐1 is a translational silencer that selectively regulates the expression of TNF‐α , 2000 .

[15]  E. Eisenberg,et al.  Intermediate oxygen exchange catalyzed by the actin-activated skeletal myosin adenosinetriphosphatase. , 1989, Biochemistry.

[16]  D. Mann,et al.  Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor , 2001, Circulation.

[17]  L. Vaca,et al.  Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. , 1993, The Journal of clinical investigation.

[18]  D. Goeddel,et al.  TNF-R1 Signaling: A Beautiful Pathway , 2002, Science.

[19]  E. Chen,et al.  Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[20]  G. Hotamisligil,et al.  Inflammatory pathways and insulin action , 2003, International Journal of Obesity.

[21]  Douglas L Mann,et al.  Stress-activated cytokines and the heart: from adaptation to maladaptation. , 2003, Annual review of physiology.

[22]  A. Saraste,et al.  Apoptosis in the heart. , 1997, The New England journal of medicine.

[23]  Geppino Falco,et al.  Identification and Functional Outcome of mRNAs Associated with RNA-Binding Protein TIA-1 , 2005, Molecular and Cellular Biology.

[24]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[25]  J. Slack,et al.  Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts. , 1996, Circulation research.

[26]  G. Nixon,et al.  Tumour necrosis factor‐α activates a calcium sensitization pathway in guinea‐pig bronchial smooth muscle , 1999 .

[27]  D. Mann,et al.  Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. , 1995, The Journal of clinical investigation.

[28]  G Baumgarten,et al.  Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. , 2000, Proceedings of the National Academy of Sciences of the United States of America.