PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice

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dc.contributor.authorStevens, Shaunaci A.en
dc.contributor.authorAguiar, Maria K. Gonzalezen
dc.contributor.authorToro, Allyson L.en
dc.contributor.authorYerlikaya, Esma I.en
dc.contributor.authorSunilkumar, Siddharthen
dc.contributor.authorVanCleave, Ashley M.en
dc.contributor.authorPfleger, Jessicaen
dc.contributor.authorBradley, Elisa A.en
dc.contributor.authorKimball, Scot R.en
dc.contributor.authorDennis, Michael D.en
dc.date.accessioned2024-02-19T20:53:25Zen
dc.date.available2024-02-19T20:53:25Zen
dc.date.issued2022-11-16en
dc.description.abstractEndoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here, we investigated the role of the stress response protein regulated in development and DNA damage 1 (REDD1) as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 wk, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to either hyperglycemic conditions or the saturated fatty acid palmitate, REDD1 expression was increased coincident with ER stress and upregulated expression of the proinflammatory cytokines IL-1β, IL-6, and TNFα. In cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions, pharmacological inhibition of the ER kinase protein kinase RNA-like endoplasmic reticulum kinase (PERK) or knockdown of the transcription factor ATF4 prevented the increase in REDD1 expression. REDD1 deletion reduced proinflammatory cytokine expression in both cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions and in the hearts of obese mice. Overall, the findings support a model wherein HFHS diet contributes to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.<b>NEW & NOTEWORTHY</b> Interplay between endoplasmic reticulum stress and inflammation contributes to cardiovascular disease progression. The studies here identify the stress response protein known as REDD1 as a missing molecular link that connects the development of endoplasmic reticulum stress with increased production of proinflammatory cytokines in the hearts of obese mice.en
dc.description.versionPublished versionen
dc.format.extentPages E62-E72en
dc.format.extent11 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1152/ajpendo.00238.2022en
dc.identifier.eissn1522-1555en
dc.identifier.issn0193-1849en
dc.identifier.issue1en
dc.identifier.orcidPfleger, Jessica [0000-0003-3263-035X]en
dc.identifier.otherPMC9870577en
dc.identifier.pmid36383638en
dc.identifier.urihttps://hdl.handle.net/10919/118059en
dc.identifier.volume324en
dc.language.isoenen
dc.publisherAmerican Physiological Societyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36383638en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectDDIT4en
dc.subjectdiabetesen
dc.subjectER stressen
dc.subjectinflammationen
dc.subjectobesityen
dc.subject.meshEndoplasmic Reticulumen
dc.subject.meshAnimalsen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshMice, Obeseen
dc.subject.meshDNA Damageen
dc.subject.meshInflammationen
dc.subject.meshProtein Kinasesen
dc.subject.mesheIF-2 Kinaseen
dc.subject.meshHeat-Shock Proteinsen
dc.subject.meshCytokinesen
dc.subject.meshActivating Transcription Factor 4en
dc.subject.meshEndoplasmic Reticulum Stressen
dc.titlePERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese miceen
dc.title.serialAmerican Journal of Physiology-Endocrinology And Metabolismen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen

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