The Ubiquitin Ligase HERC2 promotes Ang II-induced cardiac hypertrophy via destabilization of MeCP2 to enhance Lin28a expression.

HECT-type E3 ubiquitin ligases (HECT E3s) participate in the progression of cardiovascular diseases. HERC2 has been reported to play critical roles in many pathological processes, but its role in cardiac hypertrophy remains unclear. In this study, we observed that the expression and activity of HERC2 was significantly upregulated in hypertrophic hearts and angiotensin II (Ang II)-stimulated primary cardiomyocytes. Knockdown of HERC2 in cardiomyocytes significantly alleviated the myocardial hypertrophy induced by Ang II. Conversely, cardiac specific overexpression of HERC2 aggravated Ang II-induced cardiac hypertrophy in vitro and in vivo. Furthermore, we demonstrated that HERC2 promoted cardiac hypertrophy via increasing the expression of lin-28 homologue A (Lin28a), an RNA-binding protein that regulates pathological cardiac hypertrophic. Knocking down Lin28a attenuated Ang II-induced myocardial hypertrophy and abolished the increase in myocardial hypertrophy by overexpression of HERC2. Further investigation indicated that HERC2 promoted the expression level of Lin28a by reducing MeCP2, a transcriptional suppressor of Lin28a. We also showed that the pro-hypertrophic effect of HERC2 was partially dependent on MeCP2 inhibition. Mechanistically, HERC2 directly bound with MeCP2, and promoting its K48-linked polyubiquitination and degradation. Combined, these findings demonstrate HERC2 plays a crucial role in pathological cardiac hypertrophy, thereby indicating that targeting the HERC2/MeCP2/Lin28a axis is a potential strategy for heart failure therapy.
Competing Interests: The authors declare no conflict of interest.
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