# Innovative Therapy with Stem Cell-Derived Extracellular Vesicles on Cardiac Hypertrophy in an Animal Model of Atherosclerosis; Elucidation of the Molecular Mechanisms Involved in the Repair Process

## TL;DR

This study explores how stem cell-derived extracellular vesicles can reduce heart enlargement caused by atherosclerosis in hamsters.

## Contribution

The novel use of EVs from ADSCs and BMMSCs, with or without Smad2/3 siRNA, to treat cardiac hypertrophy in an atherosclerosis model is presented.

## Key findings

- EV treatment reduced cholesterol, LDL, triglycerides, TGF-β1, and Ang II levels in hypertensive–hyperlipidemic hamsters.
- EVs improved left ventricular structure and function while decreasing inflammatory markers and oxidative stress indicators.
- EVs with or without Smad2/3 siRNA diminished NF-κB p50 levels and markers of cardiac fibrosis and inflammation.

## Abstract

(1) Background: The present study investigated the effects of extracellular vesicles (EVs), derived from adipose tissue stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMMSCs), on atherosclerosis-associated cardiac hypertrophy. (2) Methodology: The experiments were performed on hamsters divided into the following groups: control (C) fed with a standard diet; hypertensive–hyperlipidemic (HH) generated by combining a diet enriched with 3% cholesterol, 15% butter, and by gavage with 8% NaCl on a daily basis; HH groups injected with EVs (ADSCs) or EVs (BMMSCs), either transfected with Smad2/3 siRNAs or not (HH-EVs (ADSCs), HH-EVs (BMMSCs), HH-EVs (ADSCs) + Smad2/3siRNA, HH-EVs (BMMSCs) + Smad2/3siRNA); and HH group injected with Smad2/3 siRNAs (HH-Smad2/3siRNA). (3) Results: In comparison with the HH group, the findings demonstrated that treatment using EVs (ADSCs or BMMSCs), either with or without Smad2/3 siRNAs, resulted in several significant improvements in the following aspects: the plasma levels of cholesterol, LDL, triglycerides, TGF-β1, and Ang II were decreased; the left ventricular structure and function were recovered; inflammatory markers, ROS, COL1A, α-SMA, Cx43, MIF, ANF, and M1/M2 macrophages, were reduced; the level of key protein NF-κB p50 was diminished. (4) Conclusions: These findings underscore the therapeutic potential of mesenchymal stem cell-derived EVs in atherosclerosis-associated cardiac hypertrophy.