The E3 ubiquitin ligase HectD3 attenuates cardiac hypertrophy and inflammation in mice
Ashraf Yusuf Rangrez1,2, Ankush Borlepawar3,4, Nesrin Schmiedel3,4
1Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, Kiel, Germany. ashraf.rangrez@uksh.de.
Insights
The E3 ubiquitin ligase HectD3 protects the heart by reducing cardiomyocyte hypertrophy and inflammation. Overexpressing HectD3 in mice improved cardiac function and reduced damage from pressure overload.
Area of Science:
- Cardiology
- Molecular Biology
- Immunology
Background:
- Myocardial inflammation is a key factor in cardiac hypertrophy and heart failure.
- The role of HECT domain E3 ubiquitin ligase 3 (HectD3) in cardiac function is currently unknown.
- HectD3 has known roles in host defense and neuroinflammation.
Purpose of the Study:
- To investigate the cardiac function of HectD3.
- To determine if HectD3 plays a role in attenuating cardiomyocyte hypertrophy and inflammation.
- To elucidate the molecular mechanisms by which HectD3 exerts its effects in the heart.
Main Methods:
- Utilized AAV9-mediated overexpression of HectD3 in mouse models.
- Assessed the impact of HectD3 on Calcineurin-NFAT signaling and LPS/interferon-γ induced inflammation.
- Investigated the regulation of cardiac substrates SUMO2 and Stat1 by HectD3.
- Evaluated cardiac hypertrophy, macrophage infiltration, and fibrosis in response to pressure overload.
Main Results:
- HectD3 overexpression attenuated Calcineurin-NFAT driven cardiomyocyte hypertrophy.
- HectD3 inhibited pro-inflammatory actions of LPS/interferon-γ via SUMO2 and Stat1.
- In vivo HectD3 overexpression reduced cardiac SUMO2/Stat1 levels, pathological hypertrophy, macrophage infiltration, and fibrosis.
- Pressure overload-induced cardiac damage was significantly reduced by HectD3.
Conclusions:
- HectD3 exhibits novel cardioprotective mechanisms by linking anti-hypertrophic and anti-inflammatory effects.
- Dual regulation of SUMO2 and Stat1 by HectD3 is central to its cardioprotective actions.
- Findings suggest a strong interplay between cardiomyocyte growth and inflammation in heart disease.
- HectD3 represents a potential therapeutic target for heart failure and cardiac hypertrophy.
Abstract:
Myocardial inflammation has recently been recognized as a distinct feature of cardiac hypertrophy and heart failure. HectD3, a HECT domain containing E3 ubiquitin ligase has previously been investigated in the host defense against infections as well as neuroinflammation; its cardiac function however is still unknown. Here we show that HectD3 simultaneously attenuates Calcineurin-NFAT driven cardiomyocyte hypertrophy and the pro-inflammatory actions of LPS/interferon-γ via its cardiac substrates SUMO2 and Stat1, respectively. AAV9-mediated overexpression of HectD3 in mice in vivo not only reduced cardiac SUMO2/Stat1 levels and pathological hypertrophy but also largely abolished macrophage infiltration and fibrosis induced by pressure overload. Taken together, we describe a novel cardioprotective mechanism involving the ubiquitin ligase HectD3, which links anti-hypertrophic and anti-inflammatory effects via dual regulation of SUMO2 and Stat1. In a broader perspective, these findings support the notion that cardiomyocyte growth and inflammation are more intertwined than previously anticipated.
