title: Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced tumor necrosis factor-α expression.
abstract: Cardiovascular events are important co-morbidities in patients with chronic inflammatory diseases like rheumatoid arthritis. Tristetraprolin (TTP) regulates pro-inflammatory processes through mRNA destabilization and therefore TTP-deficient mice (TTP(-/-) mice) develop a chronic inflammation resembling human rheumatoid arthritis. We used this mouse model to evaluate molecular signaling pathways contributing to the enhanced atherosclerotic risk in chronic inflammatory diseases. In the aorta of TTP(-/-) mice we observed elevated mRNA expression of known TTP targets like tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1α, as well as of other pro-atherosclerotic mediators, like Calgranulin A, Cathepsin S, and Osteopontin. Independent of cholesterol levels TTP(-/-) mice showed a significant reduction of acetylcholine-induced, nitric oxide-mediated vasorelaxation. The endothelial dysfunction in TTP(-/-) mice was associated with increased levels of reactive oxygen and nitrogen species (RONS), indicating an enhanced nitric oxide inactivation by RONS in the TTP(-/-) animals. The altered RONS generation correlates with increased expression of NADPH oxidase 2 (Nox2) resulting from enhanced Nox2 mRNA stability. Although TNF-α is believed to be a central mediator of inflammation-driven atherosclerosis, genetic inactivation of TNF-α neither improved endothelial function nor normalized Nox2 expression or RONS production in TTP(-/-) animals. Systemic inflammation caused by TTP deficiency leads to endothelial dysfunction. This process is independent of cholesterol and not mediated by TNF-α solely. Thus, other mediators, which need to be identified, contribute to enhanced cardiovascular risk in chronic inflammatory diseases.
authors.affiliation: From the Department of Pharmacology, Center for Thrombosis and Hemostasis, and.
authors.forename: Franziska
authors.initials: F
authors.lastname: Bollmann
authors.affiliation: From the Department of Pharmacology.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: 2nd Medical Clinic, Molecular Cardiology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.affiliation: From the Department of Pharmacology, Center for Thrombosis and Hemostasis, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Siuda
authors.affiliation: From the Department of Pharmacology.
authors.forename: Ning
authors.initials: N
authors.lastname: Xia
authors.affiliation: From the Department of Pharmacology.
authors.forename: Jenny
authors.initials: J
authors.lastname: Henke
authors.affiliation: 2nd Medical Clinic, Molecular Cardiology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.affiliation: From the Department of Pharmacology.
authors.forename: Huige
authors.initials: H
authors.lastname: Li
authors.affiliation: the Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Stumpo
authors.affiliation: the Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.affiliation: From the Department of Pharmacology, kleinert@mail.uni-mainz.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kleinert
authors.affiliation: From the Department of Pharmacology, pautz@uni-mainz.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pautz
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002908:Chronic Disease; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology*; D020871:RNA Stability / Q000502:physiology; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D014657:Vasculitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D002784:Cholesterol; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: Atherosclerosis; Endothelial Dysfunction; NADPH Oxidase; Reactive Nitrogen Species; Reactive Oxygen Species (ROS); Tumor Necrosis Factor (TNF)
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