{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:58:43Z","timestamp":1787893123302,"version":"build-2784847793"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Heart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology, which involves neuroinflammation and sympathetic activation. The crosstalk between the heart and hypothalamic microglia in HFpEF, particularly the role of small extracellular vesicles (sEVs), remains insufficiently explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      HFpEF was induced in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor\n                      <jats:sc>l<\/jats:sc>\n                      -NAME (N\u03c9-nitro-\n                      <jats:sc>l<\/jats:sc>\n                      -arginine methyl ester). Microglial depletion was achieved with PLX3397. GW4869 was administered via intraperitoneal injection. BV2 microglial cells were treated with sEVs derived from palmitate-treated HL-1 cardiomyocytes. Cardiomyocyte-specific miR-200c-3p sponge, mimic, and inhibitor were used for functional studies. The downstream target, DUSP1 (dual-specificity phosphatase 1), was validated through experimental approaches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>The HFpEF mice exhibited activation of microglia and hypothalamic inflammation. Microglial depletion suppressed sympathetic activity and improved cardiac dysfunction. sEVs derived from the myocardium of HFpEF mice induced a proinflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglial cells treated with sEVs from palmitic acid-treated HL-1 cardiomyocytes. miR-200c-3p was markedly upregulated in sEVs derived from both HFpEF myocardial tissues and palmitic acid-treated HL-1 cells, as well as within microglia themselves. Cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation, and sympathetic activation in HFpEF mice. Conversely, the miR-200c-3p mimic exacerbated proinflammatory responses in BV2 cells, while the miR-200c-3p inhibitor prevented the transition to a proinflammatory phenotype. DUSP1 was validated as a downstream target of miR-200c-3p in microglia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our study reveals that HFpEF prompts cardiomyocytes to release sEVs enriched with miR-200c-3p, leading to hypothalamic inflammation and evoking sympathetic outflow, which in turn exacerbates cardiac dysfunction. Focusing on sEV-mediated communication between cardiomyocytes and microglia may offer a new therapeutic approach for HFpEF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327765","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:00:26Z","timestamp":1784538026000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Small Extracellular Vesicles From Cardiomyocytes Activate Microglia Aggravating HFpEF"],"prefix":"10.1161","volume":"139","author":[{"given":"Lintong","family":"Men","sequence":"first","affiliation":[{"name":"Division of Cardiology, Tongji Hospital, Tongji Medical College (L.M., B.R., Y.C., M.D., S.H., D.P., X.H., L.W., S.L., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College (L.M., Q.W., B.R., Y.C., M.D., S.H., M.W., D.P., X.H., S.L., C.Z., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College (L.M., Q.W., B.R., Y.C., M.D., S.H., M.W., D.P., X.H., S.L., C.Z., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Department of Geriatrics, Tongji Hospital, Tongji Medical College (Q.W., M.W., C.Z.), Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Ren","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Tongji Hospital, Tongji Medical College (L.M., B.R., Y.C., M.D., S.H., D.P., X.H., L.W., S.L., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College (L.M., Q.W., B.R., Y.C., M.D., S.H., M.W., D.P., X.H., S.L., C.Z., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Cao","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Tongji Hospital, Tongji Medical College (L.M., B.R., Y.C., M.D., S.H., D.P., X.H., L.W., S.L., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College (L.M., Q.W., B.R., Y.C., M.D., S.H., M.W., D.P., X.H., S.L., C.Z., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Du","sequence":"additional","affiliation":[{"name":"Division of 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M.W., D.P., X.H., S.L., C.Z., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moran","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College (L.M., Q.W., B.R., Y.C., M.D., S.H., M.W., D.P., X.H., S.L., C.Z., J.L., L.L., J.G.), Huazhong University of Science and Technology, Wuhan, China."},{"name":"Department of Geriatrics, Tongji Hospital, Tongji Medical College (Q.W., M.W., C.Z.), Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China 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