title: TNF-alpha signal transduction in rat neonatal cardiac myocytes: definition of pathways generating from the TNF-alpha receptor.
abstract: Cardiomyocyte hypertrophy and apoptosis have been implicated in the loss of contractile function during heart failure (HF). Moreover, patients with HF have been shown to exhibit increased levels of tumor necrosis factor alpha (TNF-alpha) in the myocardium. However, the multiple signal transduction pathways generating from the TNF-alpha receptor in cardiomyocytes and leading preferentially to apoptosis or hypertrophy are still unknown. Here we demonstrate in neonatal rat cardiomyocytes that 1) TNF-alpha induces phosphorylation of AKT, activation of NF-kappaB, and the phosphorylation of JUN kinase; 2) blocking AKT activity prevents NF-kappaB activation, suggesting a role for AKT in regulating NF-kappaB function; 3) AKT and JUN are both critical for the hypertrophic effects of TNF-alpha, since dominant-negative mutants of these genes are capable of inhibiting TNF-alpha-induced ANF-promoter up-regulation and increase in cardiomyocyte cell size, and 4) blocking NF-kappaB, AKT, or JUN alone or in combination does not sensitize cardiomyocytes to the proapoptotic effects of TNF-alpha, in contrast to other cell types, suggesting a cardiac-specific pathway regulating the anti-apoptotic events induced by TNF-alpha. Altogether, the data presented evidence the role of AKT and JUN in TNF-alpha-induced cardiomyocyte hypertrophy and apoptosis.
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. gianluigi.condorelli@mail.tju.edu
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Carmine
authors.initials: C
authors.lastname: Morisco
authors.forename: Michael V G
authors.initials: MV
authors.lastname: Latronico
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Claudio
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Philip
authors.initials: P
authors.lastname: Tsichlis
authors.forename: Gerolama
authors.initials: G
authors.lastname: Condorelli
authors.forename: Giacomo
authors.initials: G
authors.lastname: Frati
authors.forename: Alessandra
authors.initials: A
authors.lastname: Drusco
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D009025:Morpholines; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D008156:Luciferases; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases