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Adipose-derived small extracellular vesicles exacerbate microvascular dysfunction in heart failure with preserved ejection fraction via mmu-miR-582-3p-mediated Rap1b suppression
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DOI：10.1002/inmd.70090.png)
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Abstract
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Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction despite a preserved left ventricular ejection fraction, and visceral adipose tissue is implicated in its pathogenesis. We hypothesize that VAT-derived small extracellular vesicles (sEVs) impair coronary microcirculation in HFpEF, and that the SGLT2 inhibitor canagliflozin can mitigate this effect. Using a mouse model of HFpEF established by a high-fat diet and L-NAME, we found that these mice exhibited significant coronary microcirculation dysfunction. Isolated VAT-sEVs from HFpEF mice were shown to exacerbate cardiac microvascular endothelial cell (CMEC) apoptosis and impair coronary flow reserve. Mechanistically, miRNA sequencing identified mmu-miR-582-3p as a key mediator enriched in these sEVs, which promotes CMEC apoptosis and mitochondrial dysfunction by directly targeting and downregulating Rap1b. Treatment with canagliflozin improved cardiac function, reduced CMEC apoptosis, and was associated with the downregulation of mmu-miR-582-3p in VAT-sEVs and the subsequent upregulation of Rap1b in CMECs. Our findings demonstrate that VAT-sEVs contribute to coronary microcirculation dysfunction in HFpEF via the mmu-miR-582-3p/Rap1b signaling pathway. Furthermore, the therapeutic benefit of SGLT2 inhibition is associated with modulation of this pathway; however, this association may be secondary to overall disease improvement, and a direct causal link requires future validation.
Keywords:
coronary microcirculation dysfunction
heart failure with preserved ejection fraction
miR-582-3p
small extracellular vesicles
sodium-glucose cotransporter 2 inhibitors
visceral adipose tissue
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