{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T04:47:57Z","timestamp":1782362877247,"version":"3.54.5"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, with exercise emerging as a potential non-pharmacological strategy to reduce adverse outcomes. Prior studies examining macrophage responses to exercise primarily focused on recruited C-C motif chemokine receptor 2 (CCR2\n                      <jats:sup>+<\/jats:sup>\n                      ) monocytes and macrophages in blood, adipose tissue, and skeletal muscle, but the physiological role of macrophages within the heart remains poorly defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      To determine the role of CCR2\n                      <jats:sup>+<\/jats:sup>\n                      macrophages in exercise-induced cardiac remodeling in both male and female mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We validated a voluntary exercise wheel-running model with diphtheria toxin mediated depletion of CCR2\n                      <jats:sup>+<\/jats:sup>\n                      macrophages. Cardiac remodeling was assessed using morphometric indices, echocardiography, and tissue analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Echocardiography revealed voluntary exercise increased left ventricle (LV) mass and wall thickness while preserving cardiac function compared to sedentary conditions. Exercise increased morphometric heart, LV, and right ventricle (RV) mass as well as Fulton index. Cardiomyocyte cross-sectional area was also increased in both the LV and RV of voluntary exercise mice. Cardiac remodeling occurred in both sexes, with sex-specific differences in the LV. Immunofluorescence quantification of interstitial CD68\n                      <jats:sup>+<\/jats:sup>\n                      cardiac macrophages revealed increased CCR2\n                      <jats:sup>+<\/jats:sup>\n                      macrophages and increased CCR2\n                      <jats:sup>+<\/jats:sup>\n                      to CCR2\n                      <jats:sup>\u2212<\/jats:sup>\n                      macrophage ratios in both LV and RV of voluntary exercise mice. Notably, depletion of CCR2\n                      <jats:sup>+<\/jats:sup>\n                      macrophages prevented exercise-induced cardiac hypertrophy in echocardiography, morphometric, and cardiomyocyte cross-sectional area measures. CCR2\n                      <jats:sup>+<\/jats:sup>\n                      depletion also decreased cardiomyocyte stiffness, regardless of condition, while no changes in fibrosis were observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Together, these findings identify CCR2\n                      <jats:sup>+<\/jats:sup>\n                      macrophages as required for exercise-induced cardiac remodeling and provide new insight into immune-cardiac interactions underlying adaptation to exercise.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1844427","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T04:21:42Z","timestamp":1782361302000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CCR2+ macrophages are required for exercise-induced cardiac remodeling"],"prefix":"10.3389","volume":"17","author":[{"given":"Gianni","family":"Bonnici","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan","family":"Cobb","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenna","family":"Burns","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Daigle","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Sticco-Ivins","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Hardy","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Dun","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha L.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brisa","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"Department of Biomedical Engineering, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Gu","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Kopecky","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1001\/jama.2024.15563","article-title":"Leading causes of death in the US, 2019-2023","volume":"332","author":"Ahmad","year":"2024","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1152\/jappl.2001.90.5.1900","article-title":"Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse","volume":"90","author":"Allen","year":"2001","journal-title":"J. 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