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General control nonderepressible 2 (GCN2), an eukaryotic initiation factor 2\u03b1 (eIF2\u03b1) kinase, is beneficial to the heart when it is deficiency. The current study aimed to explore whether the GCN2 is associated with cardioprotective effects in downhill running. Eight-week-old male wild type (WT) mice and GCN2 knock out (KO) mice were randomly divided into WT control (n\u2009=\u20096), WT exercise(n\u2009=\u20095), GCN2 KO control(n\u2009=\u20095), and GCN2 KO exercise(n\u2009=\u20095) groups. Mice in the exercise groups were subjected to a single session of downhill running treadmill exercise training. In WT mice, DR increased the proportion of basophils, decreased the percentage of lymphocytes in the blood, and decreased the expression of GCN2, <jats:italic>Ifn-\u03b3<\/jats:italic>, <jats:italic><jats:italic>Tgf-<\/jats:italic>\u03b2<jats:italic>r1<\/jats:italic><\/jats:italic> and immune cell markers in the myocardium. Compared with WT mice, GCN2 KO mice decreased the proportion of monocytes and neutrophils in the blood, decreased expression of <jats:italic>Ifn-\u03b3<\/jats:italic>, <jats:italic><jats:italic>Tgf-<\/jats:italic>\u03b2<jats:italic>r1<\/jats:italic><\/jats:italic> and immune cell markers, and increased expression of <jats:italic>Il-12\u03b1<\/jats:italic> in the myocardium. In GCN2 KO mice, DR increased the expression of immune cell markers in the myocardium. DR and GCN2 KO both reduced TGF-\u03b21 expression, and elevated p-eif2a expression in the myocardium. This finding demonstrated that downhill running alters inflammation and immune response in the myocardium, which is associated with GCN2.<\/jats:p>","DOI":"10.1371\/journal.pone.0329973","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T17:25:16Z","timestamp":1755883516000},"page":"e0329973","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Downhill running regulates cardiac immune response through GCN2"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-609X","authenticated-orcid":true,"given":"Xinyue","family":"Bai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0412-6126","authenticated-orcid":true,"given":"Wanting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1919-7563","authenticated-orcid":true,"given":"Xin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"issue":"8","key":"pone.0329973.ref001","doi-asserted-by":"crossref","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 heart disease and stroke statistics: a report of US and global data from the American Heart Association","volume":"149","author":"SS Martin","year":"2024","journal-title":"Circulation"},{"issue":"11","key":"pone.0329973.ref002","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.jacc.2021.01.030","article-title":"Cardiac Rehabilitation for Patients With Heart Failure: JACC Expert Panel","volume":"77","author":"B Bozkurt","year":"2021","journal-title":"J Am Coll Cardiol"},{"key":"pone.0329973.ref003","doi-asserted-by":"crossref","first-page":"842567","DOI":"10.3389\/fcvm.2022.842567","article-title":"Historical Context of Cardiac Rehabilitation: Learning From the Past to Move to the Future","volume":"9","author":"J Redfern","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"pone.0329973.ref004","doi-asserted-by":"crossref","first-page":"483","DOI":"10.3389\/fphys.2016.00483","article-title":"Moderate Load Eccentric Exercise; A Distinct Novel Training Modality","volume":"7","author":"H Hoppeler","year":"2016","journal-title":"Front Physiol"},{"issue":"10","key":"pone.0329973.ref005","doi-asserted-by":"crossref","first-page":"557","DOI":"10.2519\/jospt.2003.33.10.557","article-title":"Eccentric muscle contractions: their contribution to injury, prevention, rehabilitation, and sport","volume":"33","author":"PC LaStayo","year":"2003","journal-title":"J Orthop Sports Phys Ther"},{"issue":"10","key":"pone.0329973.ref006","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s40279-015-0373-0","article-title":"Chronic Eccentric Exercise and the Older Adult","volume":"45","author":"A Gluchowski","year":"2015","journal-title":"Sports Med"},{"key":"pone.0329973.ref007","doi-asserted-by":"crossref","first-page":"596351","DOI":"10.3389\/fphys.2020.596351","article-title":"Aerobic Metabolic Adaptations in Endurance Eccentric Exercise and Training: From Whole Body to Mitochondria","volume":"11","author":"J Touron","year":"2021","journal-title":"Front Physiol"},{"issue":"2","key":"pone.0329973.ref008","doi-asserted-by":"crossref","first-page":"288","DOI":"10.52082\/jssm.2023.288","article-title":"The health and functional benefits of eccentric versus concentric exercise training: a systematic review and meta-analysis","volume":"22","author":"M Ansari","year":"2023","journal-title":"J Sports Sci Med"},{"key":"pone.0329973.ref009","unstructured":"Liu Q. 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