title: Tumor necrosis factor receptor deficiency exacerbated Adriamycin-induced cardiomyocytes apoptosis: an insight into the Fas connection.
abstract: Cardiomyopathy is a major dose-limiting factor for applications of Adriamycin, a potent chemotherapeutic agent. The present study tested the hypothesis that increased tumor necrosis factor (TNF)-alpha signaling via its receptors protects against Adriamycin-induced cardiac injury. We used mice in which both TNF receptor I and II have been selectively inactivated (DKO) with wild-type mice as controls. Morphometric studies of cardiac tissue following Adriamycin treatment revealed greater ultrastructural damage in cardiomyocyte mitochondria from DKO mice. Biochemical studies of cardiac tissues showed cytochrome c release and the increase in proapoptotic protein levels, suggesting that lack of TNF-alpha receptor I and II exacerbates Adriamycin-induced cardiac injury. The protective role of TNF receptor I and II was directly confirmed in isolated primary cardiomyocytes. Interestingly, following Adriamycin treatment, the levels of Fas decreased in the wild-type mice. In contrast, DKO mice had an increase in Fas levels and its downstream target, mitochondrial truncated Bid. These results suggested that TNF-alpha receptors play a critical role in cardioprotection by suppression of the mitochondrial-mediated associated cell death pathway.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, 454 Health Sciences Research Building, Lexington, KY 40536, USA.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lien
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Lin
authors.forename: Ramaneeya
authors.initials: R
authors.lastname: Nithipongvanitch
authors.forename: Terry D
authors.initials: TD
authors.lastname: Oberley
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Chotiros
authors.initials: C
authors.lastname: Daosukho
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects* / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D019014:fas Receptor / Q000032:analysis / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D004317:Doxorubicin; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases