title: Age-associated differences in cardiovascular inflammatory gene induction during endotoxic stress.
abstract: Upon physiological stress, families of stress response genes are activated as natural defense mechanisms. Here, we show that induction of specific inflammatory genes is significantly dysregulated and altered in the heart of aged (24--26-month-old) versus young (4-month-old) mice experimentally challenged with a bacterial endotoxin, lipopolysaccharide (LPS, 1.5 mg/kg of body mass). Whereas the LPS-mediated induction of cardiac mRNA for tumor necrosis factor alpha or inducible nitric-oxide synthase showed no age-associated differences, the induction of interleukin-1 beta (IL-1 beta) and intracellular adhesion molecule-1 was modestly extended with aging, and the induction of IL-6 was significantly prolonged with aging. This age-associated phenomenon occurred gradually from 4 to 17 months of age and became more evident after 23 months of age. The age-associated augmentation of the cardiac IL-6 induction was also dramatic at the protein level. Immunohistochemically, the LPS-induced cardiac IL-6 was localized mainly in the microvascular walls. Aged but not young mice showed a high mortality rate during these experiments. These results demonstrate that endotoxin-mediated induction of specific inflammatory genes in cardiovascular tissues is altered with aging, which may be causally related to the increased susceptibility of aged animals to endotoxic stress.
authors.affiliation: Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555-0643, USA.
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: J
authors.initials: J
authors.lastname: Papaconstantinou
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D019446:Endotoxemia / Q000235:genetics / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000254:growth & development* / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D013312:Stress, Physiological / Q000235:genetics / Q000503:physiopathology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse