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Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury

BACKGROUND: Growth differentiation factor (GDF)‐15 is a distant and divergent member of the transforming growth factor‐β superfamily (TGF‐β) . There is growing evidence indicating the involvement of GDF‐15 in various pathologies. Expression of GDF‐15 is induced under conditions of inflammation and i...

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Autores principales: Bonaterra, Gabriel A., Zügel, Stefanie, Thogersen, Joel, Walter, Sabrina A., Haberkorn, Uwe, Strelau, Jens, Kinscherf, Ralf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540664/
https://www.ncbi.nlm.nih.gov/pubmed/23316317
http://dx.doi.org/10.1161/JAHA.112.002550
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author Bonaterra, Gabriel A.
Zügel, Stefanie
Thogersen, Joel
Walter, Sabrina A.
Haberkorn, Uwe
Strelau, Jens
Kinscherf, Ralf
author_facet Bonaterra, Gabriel A.
Zügel, Stefanie
Thogersen, Joel
Walter, Sabrina A.
Haberkorn, Uwe
Strelau, Jens
Kinscherf, Ralf
author_sort Bonaterra, Gabriel A.
collection PubMed
description BACKGROUND: Growth differentiation factor (GDF)‐15 is a distant and divergent member of the transforming growth factor‐β superfamily (TGF‐β) . There is growing evidence indicating the involvement of GDF‐15 in various pathologies. Expression of GDF‐15 is induced under conditions of inflammation and increased GDF‐15 serum levels are suggested as a risk factor for cardiovascular diseases. METHODS AND RESULTS: We show here that GDF‐15 and proinflammatory cytokine interleukin (IL)‐6 levels are highly increased (5‐fold) in cultured oxidized low‐density lipoproteins–stimulated peritoneal macrophages derived from GDF‐15(+/+)/apolipoprotein (apo) E(−/−), mice. Notably, IL‐6 induction on oxidized low‐density lipoproteins stimulation is completely abolished in the absence of GDF‐15. Consistent with our in vitro data GDF‐15 mRNA expression and protein levels are upregulated (2.5‐ to 6‐fold) in the atherosclerotic vessel wall of GDF‐15(+/+)/apoE(−/−) mice after a cholesterol‐enriched diet. GDF‐15 deficiency inhibits lumen stenosis (52%) and (18)FDG uptake (34%) in the aortic arch despite increased serum triglyceride/cholesterol levels and elevated body weight. Immunohistomorphometric investigations of atherosclerotic lesions reveal a decreased percentage of inflammatory CD11b(+) (57%) or IL‐6(+), leukocytes, and apoptotic cells (74%) after 20 weeks. However, the total number of macrophages and cell density in atherosclerotic lesions of the innominate artery are increased in GDF‐15(−/−)/apoE(−/−) mice. CONCLUSIONS: Our data suggest that GDF‐15 is involved in orchestrating atherosclerotic lesion progression by regulating apoptotic cell death and IL‐6–dependent inflammatory responses to vascular injury.
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spelling pubmed-35406642013-01-11 Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury Bonaterra, Gabriel A. Zügel, Stefanie Thogersen, Joel Walter, Sabrina A. Haberkorn, Uwe Strelau, Jens Kinscherf, Ralf J Am Heart Assoc Original Research BACKGROUND: Growth differentiation factor (GDF)‐15 is a distant and divergent member of the transforming growth factor‐β superfamily (TGF‐β) . There is growing evidence indicating the involvement of GDF‐15 in various pathologies. Expression of GDF‐15 is induced under conditions of inflammation and increased GDF‐15 serum levels are suggested as a risk factor for cardiovascular diseases. METHODS AND RESULTS: We show here that GDF‐15 and proinflammatory cytokine interleukin (IL)‐6 levels are highly increased (5‐fold) in cultured oxidized low‐density lipoproteins–stimulated peritoneal macrophages derived from GDF‐15(+/+)/apolipoprotein (apo) E(−/−), mice. Notably, IL‐6 induction on oxidized low‐density lipoproteins stimulation is completely abolished in the absence of GDF‐15. Consistent with our in vitro data GDF‐15 mRNA expression and protein levels are upregulated (2.5‐ to 6‐fold) in the atherosclerotic vessel wall of GDF‐15(+/+)/apoE(−/−) mice after a cholesterol‐enriched diet. GDF‐15 deficiency inhibits lumen stenosis (52%) and (18)FDG uptake (34%) in the aortic arch despite increased serum triglyceride/cholesterol levels and elevated body weight. Immunohistomorphometric investigations of atherosclerotic lesions reveal a decreased percentage of inflammatory CD11b(+) (57%) or IL‐6(+), leukocytes, and apoptotic cells (74%) after 20 weeks. However, the total number of macrophages and cell density in atherosclerotic lesions of the innominate artery are increased in GDF‐15(−/−)/apoE(−/−) mice. CONCLUSIONS: Our data suggest that GDF‐15 is involved in orchestrating atherosclerotic lesion progression by regulating apoptotic cell death and IL‐6–dependent inflammatory responses to vascular injury. Blackwell Publishing Ltd 2012-12-19 /pmc/articles/PMC3540664/ /pubmed/23316317 http://dx.doi.org/10.1161/JAHA.112.002550 Text en © 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. http://creativecommons.org/licenses/by/2.5/ This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Bonaterra, Gabriel A.
Zügel, Stefanie
Thogersen, Joel
Walter, Sabrina A.
Haberkorn, Uwe
Strelau, Jens
Kinscherf, Ralf
Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury
title Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury
title_full Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury
title_fullStr Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury
title_full_unstemmed Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury
title_short Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury
title_sort growth differentiation factor‐15 deficiency inhibits atherosclerosis progression by regulating interleukin‐6–dependent inflammatory response to vascular injury
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540664/
https://www.ncbi.nlm.nih.gov/pubmed/23316317
http://dx.doi.org/10.1161/JAHA.112.002550
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