Key result
TET2 knockdown in endothelial cells triggers endothelial-to-mesenchymal transition, and endothelial-specific TET2 knockout in mice aggravates pressure overload-induced cardiac hypertrophy and fibrosis.
Why the study?
DNA methylation modification plays an important role in heart diseases, but the specific role of the demethylation enzyme TET2 in cardiac remodeling remains to be investigated.
Endothelial TET2 protects against pathological cardiac remodeling by inhibiting endothelial-to-mesenchymal transition, suggesting a potential therapeutic target for cardiac fibrosis.
Answers are grounded in this paper and cite their sources.
Endothelial TET2 loss may drive cardiac remodeling via EndMT; leaves open therapeutic targeting pending human validation.
DNA methylation modification has been proved to play an important role in heart diseases. In this study, the role of Ten-Eleven Translocation-2 (TET2), which is a key demethylation enzyme, is investigated in cardiac remodeling. TET2 is abundant in endothelial cells but decreased in hypertrophic hearts. TET2 knockdown in endothelial cells triggers endothelial-to-mesenchymal transition (EndMT), while overexpression of TET2 inhibits the EndMT. In vivo, Cdh5-CreERT2/TET2 flox/flox ; Rosa26-mTmG +/- mice are developed and undergo transverse aortic constriction (TAC) subsequently to induce pathological cardiac hypertrophy model. Hearts of Cdh5-CreERT2/TET2 flox/flox mice show more severe hypertrophy and fibrosis than controls in the TAC model. Furthermore, EGLN3 is identified to participate in EndMT as the downstream target of TET2 by using RNA sequencing and whole-genome bisulfite sequencing (WGBS). Finally, vitamin C, which can mimic TET2 restoration, is found to partially improve cardiac function and inhibit myocardial fibrosis. These insights into how TET2 alleviates cardiac fibrosis may open new avenues for treating cardiac remodeling in the future.
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Kou et al. (2022) studied Cardiac remodeling and fibrosis. TET2 modulation (knockdown/overexpression) and DNA demethylation vs. Control/Sham was evaluated on Cardiac hypertrophy, fibrosis, and endothelial-to-mesenchymal transition (EndMT). TET2 knockdown in endothelial cells triggers endothelial-to-mesenchymal transition, and endothelial-specific TET2 knockout in mice aggravates pressure overload-induced cardiac hypertrophy and fibrosis.
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