TRADD-mediated pyroptosis contributes to diabetic cardiomyopathy

Area of Science:

• Cardiology
• Cell Death Mechanisms
• Molecular Biology

Background:

• Diabetic cardiomyopathy (DCM) is a leading cause of heart failure, often driven by regulated cell death pathways like pyroptosis.
• Tumor necrosis factor receptor-associated death domain protein (TRADD) is implicated in cardiovascular disorders but its role in pyroptosis during DCM is unclear.

Purpose of the Study:

• To investigate the role and underlying mechanisms of TRADD in pyroptosis within the context of diabetic cardiomyopathy.
• To explore TRADD as a potential therapeutic target for DCM.

Main Methods:

• Established streptozotocin (STZ)-induced diabetic mouse and high glucose (HG)-treated cardiomyocyte models.
• Assessed cardiac function, hypertrophy, fibrosis, and pyroptosis markers following TRADD knockdown or inhibition.
• Investigated the transcriptional regulation of TRADD by X-box binding protein 1 (XBP1) under HG conditions.

Main Results:

• TRADD expression was significantly upregulated in diabetic mouse hearts and HG-treated cardiomyocytes.
• TRADD knockdown improved cardiac function and attenuated cardiac remodeling and pyroptosis in diabetic mice.
• TRADD inhibition or knockdown reduced cell injury and pyroptosis in HG-treated cardiomyocytes.
• High glucose treatment increased XBP1 expression, which bound to the TRADD promoter, enhancing TRADD expression.

Conclusions:

• TRADD-mediated pyroptosis is a key contributor to the pathogenesis of diabetic cardiomyopathy.
• Targeting TRADD presents a promising novel therapeutic strategy for managing DCM.