OTUD1 deficiency attenuates myocardial ischemia/reperfusion induced cardiomyocyte apoptosis by regulating RACK1...

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Myocardial infarction (MI) is a growing global health concern, often complicated by ischemia/reperfusion (I/R) injury.
• Ubiquitination pathways are increasingly recognized for their role in cardiac pathophysiology.
• The specific role of Ovarian tumor deubiquitinase 1 (OTUD1) in I/R injury requires elucidation.

Purpose of the Study:

• To investigate the role and molecular mechanism of OTUD1 in myocardial I/R injury.
• To determine if OTUD1 influences cardiomyocyte apoptosis under hypoxia/reoxygenation (H/R) conditions.
• To identify potential therapeutic targets for mitigating I/R-induced heart damage.

Main Methods:

• Analysis of OTUD1 expression in I/R-induced heart tissues.
• Assessment of I/R injury and dysfunction in OTUD1-deleted mice.
• In vitro studies using cultured cardiomyocytes to examine the effects of OTUD1 manipulation on H/R-induced apoptosis.
• Immunoprecipitation-mass spectrometry to identify OTUD1-interacting proteins.
• Western blotting to analyze protein phosphorylation and signaling pathways (MAPKs, NF-κB).

Main Results:

• Myocardial OTUD1 expression was upregulated in response to I/R.
• Global deletion of OTUD1 significantly reduced I/R-induced myocardial injury and dysfunction.
• OTUD1 modulation affected H/R-induced apoptosis in cardiomyocytes.
• OTUD1 directly binds to RACK1 and enhances its phosphorylation by cleaving K63-linked polyubiquitin chains.
• This process modulates MAPKs and NF-κB signaling pathways.
• Silencing RACK1 reversed the pro-apoptotic effects of OTUD1.

Conclusions:

• OTUD1 promotes I/R-induced heart injury by deubiquitinating and enhancing RACK1 phosphorylation.
• OTUD1 acts through modulating MAPKs and NF-κB signaling.
• OTUD1 represents a potential therapeutic target for myocardial I/R injury.