Fig. 8: Scheme summarizing the finding in this study.

Our study revealed an increased EV-cargo secretion including Z-disk proteins prone to misfolding (DES, TNN), proteasome components and chaperone associated proteins by cardiomyocytes upon Wnt activation and pressure overload induced stress. This was accompanied by a concomitant activation of hypoxia response, which is known to activate EV-mediated processes. This response was more accentuated in early compensatory hypertrophic remodeling, suggesting their contribution to hypertrophic disease adaptation, and may overlap with the endosomal autophagic pathway at the formation of amphisomes, also activated upon stress. It is tempting to speculate that increased cellular stress induces protein misfolding, which triggers an excess of ubiquitination and CRYAB-mediated processes activation and the amphisomes are redirected to the exosomal release. Created with BioRender.com.