Pro-atherogenic actions of signal transducer and activator of transcription 1 serine 727 phosphorylation in LDL receptor deficient mice via modulation of plaque inflammation

Al-Ahmadi, Wijdan, Webberley, Thomas S., Joseph, Alex, Harris, Ffion, Chan, Yee-Hung, Alotibi, Reem, Williams, Jessica O., Alahmadi, Alaa, Decker, Thomas, Hughes, Timothy R. ORCID: https://orcid.org/0000-0003-2348-3490 and Ramji, Dipak P. ORCID: https://orcid.org/0000-0002-6419-5578 2021. Pro-atherogenic actions of signal transducer and activator of transcription 1 serine 727 phosphorylation in LDL receptor deficient mice via modulation of plaque inflammation. FASEB Journal 35 (10) , e21892. 10.1096/fj.202100571RR

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences
Additional Information:	This is an open access article under the terms of the Creative Commons Attribution License
Publisher:	Federation of American Society of Experimental Biology (FASEB)
ISSN:	0892-6638
Funders:	British Heart Foundation
Date of First Compliant Deposit:	30 September 2021
Date of Acceptance:	17 August 2021
Last Modified:	06 Jan 2024 02:39
URI:	https://orca.cardiff.ac.uk/id/eprint/144488

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