{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:29:02Z","timestamp":1774592942315,"version":"3.50.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Activating transcription factor 3 (ATF3) has been confirmed to be responsive to oxidative stress and to negatively regulate the activity of Toll-like receptor 4 (TLR4). However, the effect of ATF3 on cardiac microvascular ischemia\/reperfusion (I\/R) injury remains unknown. The GEO2R online tool was employed to obtain differentially expressed genes GSE4105 and GSE122020, in two rat I\/R injury microarray datasets. We established a rat myocardial I\/R model <jats:italic>in vivo<\/jats:italic>, and also generated an <jats:italic>in vitro<\/jats:italic> hypoxia\/reoxygenation (H\/R) model of cardiomyoblast H9c2 cells<jats:bold>.<\/jats:bold> Overexpression of ATF3 was achieved by adenoviral-mediated gene transfer (Ad-ATF3). Rats were randomly divided into four groups: sham, I\/R, I\/R + Ad-Lacz (as a control), and I\/R + Ad-ATF3. ELISA, CCK-8, DCFH-DA probe, qRT-PCR and Western blotting were used to determine the expression of ATF3, oxidative indices, cellular injury and TLR4\/NF-\u03baB pathway-associated proteins. Transmission electron microscopy, immunohistochemistry and immunofluorescence were used to detect the leukocyte infiltration and the alteration of microvascular morphology and function <jats:italic>in vivo<\/jats:italic>. Echocardiographic and hemodynamic data were also obtained. Bioinformatics analysis revealed that ATF3 was upregulated in I\/R myocardia in two independent rat myocardial I\/R models. Cardiac microvascular I\/R injury included leukocyte infiltration, microvascular integrity disruption, and microvascular perfusion defect, which eventually resulted in the deterioration of hemodynamic parameters and heart function. Ad-ATF3 significantly restored microvascular function, increased cardiac microvascular perfusion, and improved hemodynamic parameters and heart function. Mechanistically, Ad-ATF3 ameliorated oxidative stress, inhibited TLR4\/NF-\u03baB pathway activation and down-regulated the expression of downstream proinflammatory cytokines in I\/R myocardium <jats:italic>in vivo<\/jats:italic> and in H\/R H9c2 cells <jats:italic>in vitro<\/jats:italic>. ATF3 overexpression protects against cardiac microvascular I\/R injury in part by inhibiting the TLR4\/NF-\u03baB pathway and oxidative stress.<\/jats:p>","DOI":"10.3389\/fphar.2021.598959","type":"journal-article","created":{"date-parts":[[2021,2,21]],"date-time":"2021-02-21T01:42:51Z","timestamp":1613871771000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Overexpression of Activating Transcription Factor 3 Alleviates Cardiac Microvascular Ischemia\/Reperfusion Injury in Rats"],"prefix":"10.3389","volume":"12","author":[{"given":"Yi","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yisen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjie","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaocong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"29507","DOI":"10.1074\/jbc.M100986200","article-title":"The roles of ATF3 in glucose homeostasis. 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