Treadmill exercise ameliorates atherogenesis and vascular inflammation in ApoE−/− mice via circulating exosome-derived let-7c-5p

TL;DR

Treadmill exercise reduces atherosclerosis and inflammation in mice by altering exosome-derived miRNA levels, which in turn affects gene expression.

Contribution

This study reveals a novel mechanism by which exercise protects against atherosclerosis through exosome-derived let-7c-5p and Timp-3 regulation.

Findings

Exercise reduced plaque area and improved vascular function in atherosclerosis-prone mice.

Exercise decreased serum and arterial let-7c-5p levels, which upregulated Timp-3 expression.

Lower let-7c-5p levels were linked to reduced vascular inflammation markers like TNF-α and IL-6.

Abstract

Regular exercise training has been shown to significantly decrease atherosclerosis (AS) related mortality and hospitalization rates. Recent research has identified that circulating exosome-derived microRNAs (miRNAs) are closely related to the progression of AS through intercellular communication. But the role of exosome-derived miRNAs in exercise-mediated protection remains to be explored. This study proposes that exercise may ameliorate vascular dysfunction and plaque formation associated with AS by modulating the expression profile of exosomal miRNAs. In this study, ApoE−/− mice were used and subjected to a ten-week treadmill exercise regimen to elucidate the molecular mechanisms by which exercise influences AS, specifically through alterations in exosomal miRNAs. The results demonstrated that exercise significantly diminished plaque area and enhanced both vascular endothelium-dependent vasodilation and cardiac function in AS mice. However, no significant differences in arterial mechanical stiffness were observed. Isolation and sequencing of serum exosomes revealed a marked decrease in serum let-7c-5p levels in AS mice after exercise. Correspondingly, let-7c-5p expression in arterial vessels was significantly reduced. The negative regulatory relationship between let-7c-5p and its target gene, tissue inhibitor of metalloproteinases-3 (Timp-3), was subsequently validated through dual luciferase assays. Concurrently, an increase in Timp-3 expression in arterial vessels was observed, alongside a significant reduction in the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). Cellular experiments further corroborated the regulatory effect of let-7c-5p on Timp-3. Overall, these results suggest that exercise promotes Timp-3 expression by downregulating let-7c-5p carried by circulating exosomes, thereby mitigating atherogenesis and vascular inflammation in ApoE−/− mice.

The online version contains supplementary material available at 10.1038/s41598-025-30174-3.

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