Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy

Area of Science:

• Cardiovascular Biology
• Redox Biology
• Molecular Cardiology

Background:

• Thioredoxin 1 (Trx1) is a key cellular antioxidant with redox-sensitive cysteine residues.
• The specific contribution of Trx1 to antioxidant defense in organs remains largely uncharacterized.
• Understanding Trx1's role is vital for elucidating mechanisms of cardiac disease.

Purpose of the Study:

• To investigate the in vivo role of endogenous thioredoxin 1 (Trx1) in cardiac physiology and pathophysiology.
• To determine the impact of Trx1 inhibition on cardiac oxidative stress and hypertrophy.
• To assess the protective effects of Trx1 against pressure-induced cardiac remodeling.

Main Methods:

• Generation of cardiac-specific dominant-negative Trx1 transgenic mice (Tg-DN-Trx1).
• Assessment of oxidative stress markers and cardiac function in transgenic and nontransgenic (NTg) mice.
• Induction of cardiac hypertrophy via thoracic aortic banding (pressure overload).
• Evaluation of antioxidant treatment effects on cardiac phenotype.

Main Results:

• Tg-DN-Trx1 mice showed increased cardiac oxidative stress and hypertrophy under basal conditions.
• Antioxidant treatment normalized cardiac hypertrophy in Tg-DN-Trx1 mice.
• Pressure overload exacerbated oxidative stress and hypertrophy in Tg-DN-Trx1 mice compared to NTg mice.
• Overexpression of wild-type Trx1 protected against pressure-induced cardiac hypertrophy and oxidative stress.

Conclusions:

• Endogenous Trx1 is essential for maintaining cardiac antioxidant capacity in vivo.
• Inhibition of cardiac Trx1 promotes hypertrophy through redox-sensitive pathways.
• Trx1 plays a critical protective role against cardiac remodeling under stress.