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Published on: August 8, 2022
Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice
Jibo Han1,2,3, Liming Lin4, Zimin Fang1
1Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Insights
USP13, a deubiquitinating enzyme, protects against cardiac hypertrophy by stabilizing STAT1. This finding reveals a new therapeutic target for heart failure and ventricular dysfunction.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Cardiac hypertrophy is a precursor to ventricular dysfunction and heart failure.
- Deubiquitinating enzymes are crucial for maintaining protein stability and are implicated in myocardial hypertrophy.
Purpose of the Study:
- To investigate the role and regulatory mechanism of USP13, a cardiomyocyte-derived deubiquitinating enzyme, in cardiac hypertrophy.
- To elucidate the specific molecular pathways through which USP13 influences cardiac hypertrophy.
Main Methods:
- Utilized cardiomyocyte-specific Usp13 knockout mouse models.
- Employed Adeno-Associated Virus serotype 9 (AAV9) for USP13 overexpression in the heart.
- Performed interactome analysis to identify protein substrates.
- Assessed gene transcription and mitochondrial function in cardiomyocytes.
Main Results:
- USP13 expression was elevated in hypertrophic myocardium and localized to cardiomyocytes.
- Loss of USP13 exacerbated hypertrophy and dysfunction induced by Transverse Aortic Constriction (TAC) or Angiotensin II (Ang II) in male mice.
- USP13 overexpression demonstrated a therapeutic effect on cardiac hypertrophy in male mice.
- USP13 was found to deubiquitinate STAT1, preventing its degradation.
- USP13 enhanced STAT1-mediated Nppb gene transcription and improved mitochondrial function in cardiomyocytes.
Conclusions:
- USP13 plays a protective role in hypertrophic cardiomyocytes.
- A novel cardiomyocyte-specific USP13-STAT1 signaling axis regulates cardiac hypertrophy.
- USP13 represents a potential therapeutic target for treating cardiac hypertrophy and related heart failure.
Abstract:
Cardiac hypertrophy leads to ventricular dysfunction and heart failure. Deubiquitinating enzymes are responsible for preserving the substrate protein stability and are essential to myocardial hypertrophy. In this study, we aimed to explore the role and regulatory mechanism of a cardiomyocyte-derived deubiquitinating enzyme, USP13, in cardiac hypertrophy. Here we show that USP13 was increased in hypertrophic myocardium and was mainly distributed in cardiomyocytes. Cardiomyocyte-specific Usp13 knockout aggravated TAC or Ang II-induced myocardial hypertrophy and dysfunction in male mice. Correspondingly, USP13 overexpression by AAV9 in hearts exerted a therapeutic impact on cardiac hypertrophy in male mice. Mechanistically, we identified STAT1 as a substrate of USP13 through interactome analysis. USP13 deubiquitinated STAT1, thereby reducing its degradation. Subsequently, USP13 promoted the STAT1-targeted Nppb gene transcription and enhanced mitochondrial function in cardiomyocytes. This study illustrated a beneficial effect of USP13 in hypertrophic cardiomyocytes and identified a cardiomyocyte-specific USP13-STAT1 axis in regulating cardiac hypertrophy.
