Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α

Abstract Objective To determine the mechanisms of inflammation‐induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF‐α) in a model of systemic inflammation. Methods Seventy Sprague‐Dawley rats were divided into three groups: the control group,...

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Autores principales:	Ashmeetha Manilall, Lebogang Mokotedi, Sulè Gunter, Regina Le Roux, Serena Fourie, Colleen A. Flanagan, Aletta M.E. Millen
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	diastolic dysfunction gene expression inflammation myocardial fibrosis tumor necrosis factor alpha inhibitor Physiology QP1-981
Acceso en línea:	https://doaj.org/article/084981e9d39d49d897adb0c6dd483b61
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spelling	oai:doaj.org-article:084981e9d39d49d897adb0c6dd483b612021-11-15T09:54:40ZInflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α2051-817X10.14814/phy2.15062https://doaj.org/article/084981e9d39d49d897adb0c6dd483b612021-11-01T00:00:00Zhttps://doi.org/10.14814/phy2.15062https://doaj.org/toc/2051-817XAbstract Objective To determine the mechanisms of inflammation‐induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF‐α) in a model of systemic inflammation. Methods Seventy Sprague‐Dawley rats were divided into three groups: the control group, the collagen‐induced arthritis (CIA) group, and the anti‐TNF‐α group. Inflammation was induced in the CIA and anti‐TNF‐α groups. Following the onset of arthritis, the anti‐TNF‐α group received the TNF‐α inhibitor, etanercept, for 6 weeks. LV geometry and function were assessed with echocardiography. Circulating inflammatory markers were measured by ELISA and LV gene expression was assessed by comparative TaqMan® polymerase chain reaction. Results The LV relative gene expression of pro‐fibrotic genes, transforming growth factor β (TGFβ) (p = 0.03), collagen I (Col1) (p < 0.0001), and lysyl oxidase (LOX) (p = 0.002), was increased in the CIA group compared with controls, consistent with increased relative wall thickness (p = 0.0009). Col1 and LOX expression in the anti‐TNF‐α group were similar to controls (both, p > 0.05) and tended to be lower compared to the CIA group (p = 0.06 and p = 0.08, respectively), and may, in part, contribute to the decreased relative wall thickness in the anti‐TNF‐α group compared to the CIA group (p = 0.03). In the CIA group, the relative gene expression of matrix metalloproteinase 2 (MMP2) and MMP9 was increased compared to control (p = 0.04) and anti‐TNF‐α (p < 0.0001) groups, respectively. Conclusion Chronic systemic inflammation induces fibrosis and dysregulated LV extracellular matrix remodeling by increasing local cardiac pro‐fibrotic gene expression, which is partially mediated by TNF‐α. Inflammation‐induced LV diastolic dysfunction is likely independent of myocardial fibrosis.Ashmeetha ManilallLebogang MokotediSulè GunterRegina Le RouxSerena FourieColleen A. FlanaganAletta M.E. MillenWileyarticlediastolic dysfunctiongene expressioninflammationmyocardial fibrosistumor necrosis factor alpha inhibitorPhysiologyQP1-981ENPhysiological Reports, Vol 9, Iss 21, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	diastolic dysfunction gene expression inflammation myocardial fibrosis tumor necrosis factor alpha inhibitor Physiology QP1-981
spellingShingle	diastolic dysfunction gene expression inflammation myocardial fibrosis tumor necrosis factor alpha inhibitor Physiology QP1-981 Ashmeetha Manilall Lebogang Mokotedi Sulè Gunter Regina Le Roux Serena Fourie Colleen A. Flanagan Aletta M.E. Millen Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α
description	Abstract Objective To determine the mechanisms of inflammation‐induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF‐α) in a model of systemic inflammation. Methods Seventy Sprague‐Dawley rats were divided into three groups: the control group, the collagen‐induced arthritis (CIA) group, and the anti‐TNF‐α group. Inflammation was induced in the CIA and anti‐TNF‐α groups. Following the onset of arthritis, the anti‐TNF‐α group received the TNF‐α inhibitor, etanercept, for 6 weeks. LV geometry and function were assessed with echocardiography. Circulating inflammatory markers were measured by ELISA and LV gene expression was assessed by comparative TaqMan® polymerase chain reaction. Results The LV relative gene expression of pro‐fibrotic genes, transforming growth factor β (TGFβ) (p = 0.03), collagen I (Col1) (p < 0.0001), and lysyl oxidase (LOX) (p = 0.002), was increased in the CIA group compared with controls, consistent with increased relative wall thickness (p = 0.0009). Col1 and LOX expression in the anti‐TNF‐α group were similar to controls (both, p > 0.05) and tended to be lower compared to the CIA group (p = 0.06 and p = 0.08, respectively), and may, in part, contribute to the decreased relative wall thickness in the anti‐TNF‐α group compared to the CIA group (p = 0.03). In the CIA group, the relative gene expression of matrix metalloproteinase 2 (MMP2) and MMP9 was increased compared to control (p = 0.04) and anti‐TNF‐α (p < 0.0001) groups, respectively. Conclusion Chronic systemic inflammation induces fibrosis and dysregulated LV extracellular matrix remodeling by increasing local cardiac pro‐fibrotic gene expression, which is partially mediated by TNF‐α. Inflammation‐induced LV diastolic dysfunction is likely independent of myocardial fibrosis.
format	article
author	Ashmeetha Manilall Lebogang Mokotedi Sulè Gunter Regina Le Roux Serena Fourie Colleen A. Flanagan Aletta M.E. Millen
author_facet	Ashmeetha Manilall Lebogang Mokotedi Sulè Gunter Regina Le Roux Serena Fourie Colleen A. Flanagan Aletta M.E. Millen
author_sort	Ashmeetha Manilall
title	Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α
title_short	Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α
title_full	Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α
title_fullStr	Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α
title_full_unstemmed	Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α
title_sort	inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/084981e9d39d49d897adb0c6dd483b61
work_keys_str_mv	AT ashmeethamanilall inflammationinducedleftventricularfibrosisispartiallymediatedbytumornecrosisfactora AT lebogangmokotedi inflammationinducedleftventricularfibrosisispartiallymediatedbytumornecrosisfactora AT sulegunter inflammationinducedleftventricularfibrosisispartiallymediatedbytumornecrosisfactora AT reginaleroux inflammationinducedleftventricularfibrosisispartiallymediatedbytumornecrosisfactora AT serenafourie inflammationinducedleftventricularfibrosisispartiallymediatedbytumornecrosisfactora AT colleenaflanagan inflammationinducedleftventricularfibrosisispartiallymediatedbytumornecrosisfactora AT alettamemillen inflammationinducedleftventricularfibrosisispartiallymediatedbytumornecrosisfactora
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Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α

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