The Ubiquitin Ligase HERC2 Promotes Ang II-Induced Cardiac Hypertrophy Through Destabilization of MeCP2 to Enhance Lin28a Expression

Supplemental Digital Content is Available in the Text. Abstract: Homologous to the E6-AP carboxy terminus-type E3 ubiquitin ligases participate in the progression of cardiovascular diseases. HERC2 has been reported to play critical roles in many pathologic processes, but its role in cardiac hypertrophy remains unclear. In this study, we observed that the expression and activity of HERC2 were 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 through increasing the expression of lin-28 homologue A (Lin28a), an RNA-binding protein that regulates pathologic 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 methyl-CpG binding protein 2 (MeCP2), a transcriptional suppressor of Lin28a. We also showed that the prohypertrophic effect of HERC2 was partially dependent on MeCP2 inhibition. Mechanistically, HERC2 directly bound with MeCP2, and promotes its K48-linked polyubiquitination and degradation. Combined, these findings demonstrate that HERC2 plays a crucial role in pathologic cardiac hypertrophy, thereby indicating that targeting the HERC2/MeCP2/Lin28a axis is a potential strategy for heart failure therapy.

• Publication year

  2024

• Venue

  Journal of Cardiovascular Pharmacology

• Publication date

  2024-11-05

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1097/FJC.0000000000001647PMID 39499120
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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