Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Biochemistry

Background:

• Cardiac muscle stretch enhances force via the Frank-Starling mechanism and a slow force response (SFR).
• SFR involves reactive oxygen species (ROS) activating ERK1/2, p90RSK, and NHE1.
• ROS suppression inhibits SFR, indicating their crucial role.

Purpose of the Study:

• To investigate the effect of thioredoxin-1 (TRX1) overexpression on SFR development and NHE1 phosphorylation.
• To determine if enhanced antioxidant capacity via TRX1 impacts stretch-induced cardiac responses.

Main Methods:

• Comparison of wild-type (WT) and TRX1-overexpressing mice.
• Isolated papillary muscle experiments involving controlled stretch (92-98% of maximal length).
• Assessment of basal and stretch-induced phosphorylation of ERK1/2, p90RSK, and NHE1.

Main Results:

• TRX1 overexpression did not alter basal ERK1/2, p90RSK, or NHE1 levels.
• A significant SFR was observed in WT mice but completely abolished in TRX1-overexpressing mice.
• Myocardial stretch increased NHE1 phosphorylation in WT mice, an effect absent in TRX1-overexpressing mice.

Conclusions:

• Overexpression of TRX1 significantly blunts the slow force response in cardiac muscle.
• Enhanced cardiac antioxidant defense via TRX1 prevents stretch-induced NHE1 phosphorylation and activation.
• TRX1 may serve as a therapeutic target for modulating cardiac contractility post-stretch.