Pharmacology, pharmacogenomics, drug discovery and design, drug therapy
Aberrant Wnt activation has been reported in failing cardiomyocytes. Here we present
single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific
Wnt activation (β-cat Δex3 ) as well as with compensatory and failing hypertrophic
remodeling. We show that functional enrichment analysis points to an involvement of
extracellular vesicles (EVs) related processes in hearts of β-cat Δex3 mice. A proteomic
analysis of in vivo cardiac derived EVs from β-cat Δex3 hearts has identified differentially
enriched proteins involving 20 S proteasome constitutes, protein quality control (PQC),
chaperones and associated cardiac proteins including α-Crystallin B (CRYAB) and sarcomeric
components. The hypertrophic model confirms that cardiomyocytes reacted with an acute
early transcriptional upregulation of exosome biogenesis processes and chaperones
transcripts including CRYAB, which is ameliorated in advanced remodeling. Finally,
human induced pluripotent stem cells (iPSC)-derived cardiomyocytes subjected to pharmacological
Wnt activation recapitulated the increased expression of exosomal markers, CRYAB accumulation
and increased PQC signaling. These findings reveal that secretion of EVs with a proteostasis
signature contributes to early patho-physiological adaptation of cardiomyocytes, which
may serve as a read-out of disease progression and can be used for monitoring cellular
remodeling in vivo with a possible diagnostic and prognostic role in the future.
