Cardiomyocyte-derived small extracellular vesicle-transported let-7b-5p modulates cardiac remodeling via TLR7 signaling pathway.

Cardiac remodeling is the major pathological change of heart failure. And let-7 family has been implicated in the development and pathogenesis of cardiovascular diseases. However, the mechanisms underlying let-7b-5p-mediated cellular pathogenesis of cardiac remodeling are not well understood. The present study aimed to explore the effects of let-7b-5p on cardiac remodeling and the corresponding regulatory mechanism. In vivo results indicated that cardiac let-7b-5p was upregulated in the mouse model of Angiotensin II (Ang II)-induced cardiac remodeling. Additionally, let-7b-5p knockdown ameliorated the effects of Ang II-induced cardiac remodeling, whereas let-7b-5p overexpression facilitated cardiac remodeling. In vitro, let-7b-5p mimics induced cardiomyocyte hypertrophy, fibroblast transdifferentiation, and the expression of inflammatory factors in neonatal mouse cardiomyocytes (NMCMs), neonatal mouse cardiac fibroblasts (NMCFs), and bone marrow-derived macrophages (BMDMs), respectively. Furthermore, let-7b-5p exerted its cardiac pro-remodeling effects at least partially through a small extracellular vesicle (SEV)-based delivery strategy. We found that let-7b-5p was enriched in SEVs derived from Ang II-treated NMCMs (NMCM-SEV) but not from Ang II-treated NMCFs (NMCF-SEV). Mechanistic analyses revealed that NMCM-SEV promoted TLR7 and MyD88 expression, which increased NF-κB phosphorylation levels. Knockdown of let-7b-5p, TLR7 or MyD88 in NMCMs, NMCFs, and BMDMs abolished the cardiac pro-remodeling effects of NMCM-SEV. These results uncover that let-7b-5p-containing NMCM-SEVs promote cardiac remodeling via the TLR7/MyD88/NF-κB pathway, implicating let-7b-5p as a potential therapeutic target for heart failure.