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

Sep 30, 2026

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Regular exercise training reduces atherosclerosis-related mortality and hospitalization, yet how it modulates circulating exosome-derived microRNAs (miRNAs) remains unclear. Using ApoE−/− mice subjected to a ten-week treadmill regimen, the study shows smaller plaque area and improved endothelial-dependent vasodilation and cardiac function, without clear changes in arterial stiffness. Serum exosome sequencing reveals reduced let-7c-5p, lowered arterial let-7c-5p, and validated let-7c-5p repression of Timp-3. Inflammatory mediators TNF-α, IL-6, and MMP-9 decrease, supported by cellular evidence.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Background

Exercise training and atherosclerosis

MicroRNAs and exosome-mediated communication

Study Design and Methods

ApoE−/− treadmill exercise regimen

Exosome isolation and miRNA sequencing

Dual luciferase and cellular validation

Results

Plaque, vascular function, and cardiac function

let-7c-5p reduction in serum exosomes and vessels

Timp-3 regulation and inflammatory factor changes

Conclusion

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Treadmill exercise amelioratesatherogenesis and vascular inflammation inApoE −/− mice via circulating exosome-derived let-7c- 5p Wenhuang Guo1,3, Jinyun Wang1,3, Zaoshang Chang2,3, Shuo Lin1, Guangyuan Sha1, Shen Wang1, Junhao Huang1􀀍, Min Hu1􀀍 & JingboXia1􀀍 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 regimento 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 inTimp-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 onTimp-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 inApoE−/− mice. Keywords Treadmill exercise, Atherosclerosis, let-7c-5p, Timp-3, Vascular inflammation Abbreviations ACh Acetylcholine ApoE Apolipoprotein E AS Atherosclerosis CEM Collagen elastic modulus CO Cardiac output ECM Extracellular matrix EEM Elastin elastic modulus EF Ejection fraction FS Fractional shortening H&E Hematoxylin-eosin 1Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion, Guangzhou Sport University, Guangzhou 510500, China. 2Department of Physiology, Shaoyang University, Shaoyang, China. 3Wenhuang Guo, Jinyun Wang and Zaoshang Chang contributed equally to this work. 􀀍 [email: junhaohuang2006@hotmail.com](email: junhaohuang2006@hotmail.com); [whoomin@aliyun.com](whoomin@aliyun.com); [xiajb@gzsport.edu.cn](xiajb@gzsport.edu.cn) [www. nature.com/scientificreports/](www. nature.com/scientificreports/) IL-6 miRNAMMPMOVASNTAox-LDLPWV qRT-PCR siRNATEM Timp TNF-α VSMCs Interleukin-6 MicroRNA Matrix metalloproteinase Mouse aortic smooth muscle cells Nanoparticle tracking analysis Oxidized low-density lipoprotein Pulse wave velocity Quantitative real-time polymerase chain reaction Small interfering RNA Transmission electron microscope Tissue inhibitor of metalloproteinase Tumor necrosis factor-α Vascular smooth muscle cells Atherosclerosis (AS), a complex chronic inflammatory disease, is characterized by lipid deposition in arterial walls that leads to hardening and narrowing of arteries. AS has been recognized as a major contributor to cardiovascular diseases, which is the leading cause of death around the world1. AS affects cardiovascular health through multiple mechanisms including endothelial d

FAQs

How does treadmill exercise affect atherosclerosis in ApoE−/− mice?

Exercise training decreases plaque area and improves endothelial-dependent vasodilation and cardiac function in atherosclerotic mice.

What change in exosome-derived miRNAs is linked to exercise protection?

Serum exosome profiling shows a marked reduction in let-7c-5p levels after exercise, mirrored by reduced let-7c-5p expression in arterial vessels.

How is the let-7c-5p–Timp-3 relationship validated?

The study confirms let-7c-5p negatively regulates Timp-3 using dual luciferase assays, and cellular experiments further support the regulatory effect.

Sep 30, 2026

Upload by Levi