{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE334nnn/GSE334160/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Mus musculus"],"gds_type":["Non-coding RNA profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE334160"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Small Extracellular Vesicles Secreted from Cardiomyocytes Targeting Microglial Activation and Hypothalamic Inflammation Aggravate HFpEF","description":"Background: Heart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology that 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. Methods and Results: We constructed a HFpEF model in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor L-NAME. These mice exhibited activation of microglia and hypothalamic inflammation. Microglia depletion with PLX3397 suppressed sympathetic activity and improved cardiac dysfunction in HFpEF. sEVs derived from the myocardium of HFpEF mice induced a pro-inflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of the sEVs biogenesis inhibitor GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglia treated with sEVs isolated from palmitic acid-treated HL-1 cardiomyocytes. Bioinformatic and RT-qPCR analyses revealed a notable upregulation of miR-200c-3p in sEVs derived from both HFpEF myocardial tissue and palmitic acid- treated HL-1 cardiomyocytes, as well as in microglia. Cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation and sympathetic activation in HFpEF mice. Conversely, miR-200c-3p mimic exacerbated pro-inflammatory responses in BV2, while miR-200c-3p inhibitor prevented the transition to a pro-inflammatory phenotype. The anti-inflammatory protein DUSP1 was validated as a potential downstream target of miR-200c-3p in microglia. Conclusions: 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.","dates":{"publication":"2026/07/01"},"accession":"GSE334160","cross_references":{"GSM":["GSM9782472","GSM9782471","GSM9782470","GSM9782466","GSM9782465","GSM9782464","GSM9782463","GSM9782469","GSM9782468","GSM9782467"],"GPL":["28330"],"GSE":["334160"],"taxon":["Mus musculus"]}}