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Published on: June 3, 2018
OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes
Mengyang Wang1,2,3, Xue Han1,2, Tianxiang Yu2
1Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
Abstract:
Rationale: Understanding the molecular mechanisms of deleterious cardiac remodeling is important for the development of treatments for heart failure. Recent studies have highlighted a role of deubiquitinating enzymes in cardiac pathophysiology. In the present study, we screened for alteration of deubiquitinating enzymes in experimental models of cardiac remodeling, which indicated a potential role of OTU Domain-Containing Protein 1 (OTUD1). Methods: Wide-type or OTUD1 knockout mice with chronic angiotensin II infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodeling and heart failure. We also overexpressed OTUD1 in mouse heart with AAV9 vector to validate the function of OTUD1. LC-MS/MS analysis combined with Co-IP was used to identify the interacting proteins and substrates of OTUD1. Results: We found that OTUD1 is elevated in mouse heart tissues following chronic angiotensin II administration. OTUD1 knockout mice were significantly protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis and inflammatory response. Similar results were obtained in the TAC model. Mechanistically, OTUD1 bounds to the SH2 domain of STAT3 and causes deubiquitination of STAT3. Cysteine at position 320 of OTUD1 exerts K63 deubiquitination to promote STAT3 phosphorylation and nuclear translocation, thereby increasing STAT3 activity to induce inflammatory responses, fibrosis, and hypertrophy in cardiomyocytes. Finally, OTUD1 overexpression by AAV9 vector increases Ang II-induced cardiac remodeling in mice and OTUD1-regulated responses can be inhibited by blocking STAT3. Conclusion: Cardiomyocyte OTUD1 promotes pathological cardiac remodeling and dysfunction by deubiquitinating STAT3. These studies have highlighted a novel role of OTUD1 in hypertensive heart failure and identified STAT3 as a target of OTUD1 in mediating these actions.
Insights
OTU Domain-Containing Protein 1 (OTUD1) promotes heart failure by deubiquitinating STAT3, leading to cardiac remodeling and dysfunction. Blocking STAT3 inhibits these detrimental effects, offering a potential therapeutic target for hypertensive heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Biochemistry
Background:
- Cardiac remodeling is a key factor in heart failure development.
- Deubiquitinating enzymes are increasingly recognized for their role in cardiac pathophysiology.
- OTU Domain-Containing Protein 1 (OTUD1) was identified as a potential player in cardiac remodeling.
Purpose of the Study:
- To investigate the role of OTUD1 in pathological cardiac remodeling and heart failure.
- To elucidate the molecular mechanisms by which OTUD1 influences cardiac function.
- To identify potential therapeutic targets for heart failure related to OTUD1 activity.
Main Methods:
- Utilized OTUD1 knockout and wild-type mice subjected to chronic angiotensin II infusion and transverse aortic constriction (TAC) models.
- Employed adeno-associated virus serotype 9 (AAV9) for cardiac-specific OTUD1 overexpression.
- Applied Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) and Co-immunoprecipitation (Co-IP) to identify OTUD1 interacting proteins and substrates.
- Investigated the effect of blocking STAT3 on OTUD1-mediated responses.
Main Results:
- OTUD1 expression was elevated in mouse hearts under angiotensin II administration.
- OTUD1 knockout mice showed significant protection against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis, and inflammation.
- OTUD1 deubiquitinates STAT3 at cysteine 320, promoting its phosphorylation, nuclear translocation, and subsequent activation, which drives cardiomyocyte hypertrophy, fibrosis, and inflammation.
- OTUD1 overexpression exacerbated angiotensin II-induced cardiac remodeling, and these effects were mitigated by STAT3 inhibition.
Conclusions:
- Cardiomyocyte OTUD1 significantly promotes pathological cardiac remodeling and dysfunction in heart failure.
- OTUD1 acts by deubiquitinating STAT3, thereby enhancing its pro-inflammatory and pro-fibrotic signaling.
- OTUD1 represents a novel therapeutic target in hypertensive heart failure, with STAT3 being a key mediator of its actions.
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