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It remains unclear whether exosomes derived from healthy cardiac fibroblasts affect I\/R injury and, if so, what are the underlying mechanisms?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Cardiac fibroblasts were isolated from neonatal rats, adult rats and adult rats subjected to I\/R. Their exosomes were designated as follows: neonatal cardiac fibroblasts (N\u2010Exo), adult rat cardiac fibroblasts (A\u2010Exo) and cardiac fibroblasts in a remote non\u2010ischaemic area (R\u2010Exo). Apoptosis of cardiomyocytes and the role of a cluster of microRNAs from exosomes in I\/R injury were investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>N\u2010Exo, A\u2010Exo and R\u2010Exo were taken up by ischaemic cardiomyocytes through clathrin heavy chain (Cltc)\u2010mediated endocytosis, enhancing cardiomyocyte apoptosis and increasing myocardial infarct size in rats and mice. Inhibiting Cltc\u2010mediated endocytosis with chlorpromazine reduced the pro\u2010apoptotic effects of N\u2010Exo in neonatal rat cardiomyocytes under anoxia\/reoxygenation. A functional cluster of miRNAs (miR\u20109a\u20105p, miR\u201092b\u20103p, miR\u2010181a\u20105p, miR\u2010494\u20103p and miR\u2010708\u20105p) from exosomes was identified and promoted cardiomyocyte apoptosis via a common gene, Rap1b. R\u2010Exo downregulated cardiac Rap1b and Bcl2 in I\/R rats. Mimics of these miRNAs reduced luciferase activity of the Rap1b gene and were blocked by site\u2010directed mutagenesis of the Rap1b gene at miRNAs binding sites. Co\u2010immunoprecipitation demonstrated that Rap1b protein bound to ERK1\/2 and Cltc.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Exosomes from non\u2010ischaemic fibroblasts worsen I\/R injury by promoting apoptosis of ischaemic cardiomyocytes through a cluster of miRNAs targeting the Rap1b\/ERK1\/2 pathway, highlighting Rap1b restoration as a potential therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70249","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T16:57:32Z","timestamp":1763139452000},"page":"1186-1204","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A fibroblast\u2010specific miRNA functional cluster in remote exosomes aggravates myocardial ischaemia\/reperfusion injury via the Rap1b\/ERK1\/2 axis"],"prefix":"10.1111","volume":"183","author":[{"given":"Rui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation Nanfang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation Nanfang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiarui","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation Nanfang Hospital, Southern Medical University  Guangzhou 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