{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:12:35Z","timestamp":1792253555753,"version":"4.4.0"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100013058","name":"Key Research and Development Program of Jiangsu Province","doi-asserted-by":"publisher","award":["BE2021735"],"award-info":[{"award-number":["BE2021735"]}],"id":[{"id":"10.13039\/501100013058","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Provincial Medical Key Discipline","award":["ZDXK202207"],"award-info":[{"award-number":["ZDXK202207"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81670326"],"award-info":[{"award-number":["81670326"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Zhongda Hospital Affiliated to Southeast University"},{"name":"Jiangsu Province High-Level Hospital Pairing Assistance Construction Funds","award":["zdlyg11"],"award-info":[{"award-number":["zdlyg11"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Acute myocardial infarction results in significant mortality and chronic heart failure, with reperfusion frequently inducing myocardial ischaemia-reperfusion (IR) injury mediated by infiltrating monocytes and monocyte-derived macrophages (iMacs). The olfactory receptor 2 (Olfr2) is hypothesized to serve as a pivotal inflammatory mediator in this context. This study aimed to elucidate the regulatory role of Olfr2 in mitochondrial homeostasis and inflammation in iMacs during myocardial IR injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>The surface expression of OR6A2 (human ortholog of Olfr2) on monocyte subsets was assessed to determine its association with major adverse cardiovascular events (MACEs) in IR-injured patients. The mechanistic role of Olfr2 in modulating iMacs during myocardial IR injury was investigated using both in vivo and in vitro interventions targeting Olfr2. Elevated OR6A2 levels on human monocytes and octanal, an OR6A2 agonist, were significantly associated with an increased risk of MACEs and correlated with increased oxidative stress and pro-inflammatory responses in patients with IR injury. The genetic ablation of Olfr2 in mice demonstrated significant attenuation of mitochondrial reactive oxygen species (mtROS) and pro-inflammatory cytokine in iMacs, accompanied by diminished immune cell infiltration and reduced cardiomyocyte apoptosis, ultimately ameliorating myocardial IR injury. Mechanistically, Olfr2 activated nuclear receptor subfamily 4 group A member 1 (NR4A1) via cAMP\/PKA signalling, promoting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which led to mitochondrial mtROS overproduction, mitochondrial membrane potential disruption, mitochondrial apoptosis, and the subsequent release of pro-inflammatory factors through NLRP3 inflammasome activation. Notably, monocyte\/macrophage-specific NR4A1 overexpression in Olfr2 knockout mice negated the cardiovascular protection observed during IR injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Elevated OR6A2 expression and octanal levels were significantly associated with an increased risk of MACEs. Our findings identified the Olfr2\/cAMP\/PKA\/NR4A1 axis as a novel signalling pathway contributing to cardiac IR injury by promoting Drp1-mediated mitochondrial fission and subsequent production of pro-inflammatory cytokines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf232","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:58:43Z","timestamp":1762865923000},"page":"2759-2776","source":"Crossref","is-referenced-by-count":4,"title":["Targeting olfactory receptor 2 on monocytes for cardioprotection against myocardial ischaemia-reperfusion injury via NR4A1-mediated mitochondrial fission"],"prefix":"10.1093","volume":"121","author":[{"given":"Yahao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiandong","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orion I R Chiara","family":"Villamil","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genshan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Zhongda Hospital, Southeast University , 87 Dingjiaqiao, Nanjing 210009 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"2025123108470239700_cvaf232-B1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1093\/eurheartj\/ehx393","article-title":"2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the 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