Pro-atherogenic actions of signal transducer and activator of transcription 1 serine 727 phosphorylation in LDL receptor deficient mice via modulation of plaque inflammation
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology..
Atherosclerosis is a chronic inflammatory disorder of the vasculature regulated by cytokines. We have previously shown that extracellular signal-regulated kinase-1/2 (ERK1/2) plays an important role in serine 727 phosphorylation of signal transducer and activator of transcription-1 (STAT1) transactivation domain, which is required for maximal interferon-γ signaling, and the regulation of modified LDL uptake by macrophages in vitro. Unfortunately, the roles of ERK1/2 and STAT1 serine 727 phosphorylation in atherosclerosis are poorly understood and were investigated using ERK1 deficient mice (ERK2 knockout mice die in utero) and STAT1 knock-in mice (serine 727 replaced by alanine; STAT1 S727A). Mouse Atherosclerosis RT² Profiler PCR Array analysis showed that ERK1 deficiency and STAT1 S727A modification produced significant changes in the expression of 18 and 49 genes, respectively, in bone marrow-derived macrophages, with 17 common regulated genes that included those that play key roles in inflammation and cell migration. Indeed, ERK1 deficiency and STAT1 S727A modification attenuated chemokine-driven migration of macrophages with the former also impacting proliferation and the latter phagocytosis. In LDL receptor deficient mice fed a high fat diet, both ERK1 deficiency and STAT1 S727A modification produced significant reduction in plaque lipid content, albeit at different time points. The STAT1 S727A modification additionally caused a significant reduction in plaque content of macrophages and CD3 T cells and diet-induced cardiac hypertrophy index. In addition, there was a significant increase in plasma IL-2 levels and a trend toward increase in plasma IL-5 levels. These studies demonstrate important roles of STAT1 S727 phosphorylation in particular in the regulation of atherosclerosis-associated macrophage processes in vitro together with plaque lipid content and inflammation in vivo, and support further assessment of its therapeutical potential.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:35 |
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| Enthalten in: |
FASEB journal : official publication of the Federation of American Societies for Experimental Biology - 35(2021), 10 vom: 02. Okt., Seite e21892 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Al-Ahmadi, Wijdan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.10.2021 Date Revised 15.10.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1096/fj.202100571RR |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM331112914 |
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| 100 | 1 | |a Al-Ahmadi, Wijdan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Pro-atherogenic actions of signal transducer and activator of transcription 1 serine 727 phosphorylation in LDL receptor deficient mice via modulation of plaque inflammation |
| 264 | 1 | |c 2021 | |
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| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. | ||
| 520 | |a Atherosclerosis is a chronic inflammatory disorder of the vasculature regulated by cytokines. We have previously shown that extracellular signal-regulated kinase-1/2 (ERK1/2) plays an important role in serine 727 phosphorylation of signal transducer and activator of transcription-1 (STAT1) transactivation domain, which is required for maximal interferon-γ signaling, and the regulation of modified LDL uptake by macrophages in vitro. Unfortunately, the roles of ERK1/2 and STAT1 serine 727 phosphorylation in atherosclerosis are poorly understood and were investigated using ERK1 deficient mice (ERK2 knockout mice die in utero) and STAT1 knock-in mice (serine 727 replaced by alanine; STAT1 S727A). Mouse Atherosclerosis RT² Profiler PCR Array analysis showed that ERK1 deficiency and STAT1 S727A modification produced significant changes in the expression of 18 and 49 genes, respectively, in bone marrow-derived macrophages, with 17 common regulated genes that included those that play key roles in inflammation and cell migration. Indeed, ERK1 deficiency and STAT1 S727A modification attenuated chemokine-driven migration of macrophages with the former also impacting proliferation and the latter phagocytosis. In LDL receptor deficient mice fed a high fat diet, both ERK1 deficiency and STAT1 S727A modification produced significant reduction in plaque lipid content, albeit at different time points. The STAT1 S727A modification additionally caused a significant reduction in plaque content of macrophages and CD3 T cells and diet-induced cardiac hypertrophy index. In addition, there was a significant increase in plasma IL-2 levels and a trend toward increase in plasma IL-5 levels. These studies demonstrate important roles of STAT1 S727 phosphorylation in particular in the regulation of atherosclerosis-associated macrophage processes in vitro together with plaque lipid content and inflammation in vivo, and support further assessment of its therapeutical potential | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a LDL receptor deficient mice | |
| 650 | 4 | |a atherosclerosis | |
| 650 | 4 | |a extracellular signal-regulated kinase 1/2 | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a signal transducer and activator of transcription-1 | |
| 650 | 7 | |a Receptors, LDL |2 NLM | |
| 650 | 7 | |a STAT1 Transcription Factor |2 NLM | |
| 650 | 7 | |a Stat1 protein, mouse |2 NLM | |
| 700 | 1 | |a Webberley, Thomas S |e verfasserin |4 aut | |
| 700 | 1 | |a Joseph, Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Harris, Ffion |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Yee-Hung |e verfasserin |4 aut | |
| 700 | 1 | |a Alotibi, Reem |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Jessica O |e verfasserin |4 aut | |
| 700 | 1 | |a Alahmadi, Alaa |e verfasserin |4 aut | |
| 700 | 1 | |a Decker, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Hughes, Timothy R |e verfasserin |4 aut | |
| 700 | 1 | |a Ramji, Dipak P |e verfasserin |4 aut | |
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