Metabolic status differentiates Trp53inp2 function in pressure-overload induced heart failure

Area of Science:

• Cardiology
• Molecular Biology
• Metabolic Disorders

Background:

• Cardiometabolic disorders, including hypertension, obesity, and diabetes, are a growing global health burden.
• Tumor Protein p53-inducible Nuclear Protein 2 (Trp53inp2) is implicated as a link between hyperglycemia and cardiac hypertrophy.
• The in vivo role of Trp53inp2 in cardiac pathology remains undetermined.

Purpose of the Study:

• To investigate the role of Trp53inp2 in cardiac pathology under mechanical and metabolic stress.
• To determine the impact of cardiac-specific Trp53inp2 inactivation on heart failure development.
• To elucidate the effects of Trp53inp2 on glucose metabolism in the heart.

Main Methods:

• Generation of a cardiac-specific knockout model of Trp53inp2 (Trp53inp2-cKO) in mice.
• Assessment of cardiac function using echocardiography under pressure-overload and combined high-fat diet/pressure-overload conditions.
• Analysis of gene expression related to heart failure markers and glucose metabolism.

Main Results:

• Trp53inp2 inactivation accelerated heart failure with reduced ejection fraction and elevated heart failure markers under pressure-overload.
• Conversely, Trp53inp2 inactivation ameliorated cardiac dysfunction in a cardiometabolic disorder model (high-fat diet plus pressure overload).
• Trp53inp2 inactivation altered glucose metabolism gene expression differently depending on the stress conditions.

Conclusions:

• Cardiomyocyte Trp53inp2 exhibits opposing roles in heart failure pathogenesis and glucose regulation under distinct stress conditions.
• Trp53inp2 may exacerbate cardiac dysfunction during pressure overload but offer protection in cardiometabolic disease.
• These findings highlight Trp53inp2 as a potential therapeutic target with context-dependent effects in cardiovascular and metabolic diseases.