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The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor

Hai-Lian Bi1, Xiao-Li Zhang2, Yun-Long Zhang1

  • 1Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 11600, China.

Science Advances
|June 5, 2020
PubMed

Insights

Ubiquitin C-terminal hydrolase 1 (UCHL1) promotes cardiac hypertrophy by stabilizing epidermal growth factor receptor (EGFR). Inhibiting UCHL1 reversed pathological cardiac hypertrophy, suggesting UCHL1 as a therapeutic target for heart failure.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Pathological cardiac hypertrophy is a precursor to heart failure.
  • The ubiquitin-proteasome system (UPS) is crucial for cardiac protein homeostasis.
  • Deubiquitinating enzymes (DUBs) roles in cardiac function are under-researched.

Purpose of the Study:

  • Investigate the role of deubiquitinating enzyme UCHL1 in cardiac hypertrophy.
  • Determine the molecular mechanism by which UCHL1 affects cardiac hypertrophy.
  • Evaluate UCHL1 as a potential therapeutic target for hypertrophic heart disease.

Main Methods:

  • Assessed UCHL1 expression in cardiomyocytes and hypertrophic/failing hearts.
  • Utilized UCHL1 knockdown and overexpression in vitro and in vivo models.
  • Examined UCHL1 interaction with epidermal growth factor receptor (EGFR).
  • Administered UCHL1 inhibitor LDN-57444 in vivo.

Main Results:

  • UCHL1 was significantly upregulated in hypertrophic and failing hearts.
  • UCHL1 knockdown ameliorated cardiac hypertrophy; overexpression exacerbated it.
  • UCHL1 deubiquitinated and stabilized EGFR, activating downstream signaling.
  • UCHL1 inhibition reversed cardiac hypertrophy and remodeling.

Conclusions:

  • UCHL1 positively regulates cardiac hypertrophy via EGFR stabilization.
  • UCHL1 is a key mediator in the development of pathological cardiac hypertrophy.
  • Targeting UCHL1 offers a promising therapeutic strategy for heart failure.

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