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| Item Type: | Article |
|---|---|
| Title: | Small extracellular vesicle-mediated adipocyte-cardiomyocyte crosstalk exacerbates heart failure with preserved ejection fraction |
| Creators Name: | Pan, Qi, Chen, Cheng, Zhang, Ce, Jiang, Yao, Zhou, Ziqin, Zhang, Han, Gillette, Thomas G., Hill, Joseph A., Schiattarella, Gabriele G., Wu, Guixin, Yang, Yuejin and Chen, Guihao |
| Abstract: | Aims: Although growing evidence suggests that obesity/central adiposity predispose to development and exacerbation of heart failure with preserved ejection fraction (HFpEF), it remains to be clarified whether there is a causal relationship between adiposity and HFpEF pathogenesis. Methods and results: HFpEF was induced in male, C57BL/6N mice using high-fat diet + Nω-nitro-l-arginine methyl ester. Resection or transplantation of visceral adipose tissue (VAT) blunted or exacerbated HFpEF phenotypes, respectively, the in mice. VAT from HFpEF mice displayed greater weight and secreted more small extracellular vesicles (sEVs) than those from chow-fed mice. Either systemic inhibition of sEV secretion or VAT-specific knockdown of Rab27b (an indispensable GTPase for sEV secretion) protected against HFpEF. Discovery-driven experiments identified miR-2953p within sEVs as a possible mediator of the VAT-heart axis, which impaired cardiac autophagy by binding to Ulk1 mRNA. MiR-295-3p antagomir treatment mitigated HFpEF phenotypes. Additionally, neonatal mouse cardiomyocytes (NMCMs) manifested blunted autophagic flux after treatment with plasma sEVs from HFpEF mice. Notably, HFpEF patients displayed downregulated cardiac Ulk1 and autophagy compared with healthy individuals. Restoration of cardiac autophagy with rapamycin or ULK1 overexpression via AAV-9 attenuated the HFpEF phenotype in mice. Conclusions: The present work unveils a mechanism whereby obesity promotes HFpEF progression, emphasizing the role of VAT-heart crosstalk. Specifically, VATderived sEVs, miR-295-3p, and the resultant disruption of cardiac autophagy contribute significantly to the pathogenesis of HFpEF. |
| Keywords: | Heart Failure with Preserved Ejection Fraction, Obesity, Visceral Adipose Tissue, Small Extracellular Vesicles, Autophagy, Animals, Mice |
| Source: | Cardiovascular Research |
| ISSN: | 0008-6363 |
| Publisher: | Oxford University Press |
| Page Range: | cvag030 |
| Date: | 5 February 2026 |
| Official Publication: | https://doi.org/10.1093/cvr/cvag030 |
| PubMed: | View item in PubMed |
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