Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac...

Area of Science:

• Cardiology
• Endocrinology
• Molecular Biology

Background:

• Thyroid hormone (TH) is crucial for heart function, but its metabolism is often disrupted in heart disease, mimicking hypothyroidism.
• Current TH therapy for heart disease lacks clear benefits, potentially due to peripheral TH actions.
• Understanding localized TH metabolism in the heart is key to developing effective cardiac treatments.

Purpose of the Study:

• To investigate the potential of enhancing cardiac TH metabolism for treating heart disease.
• To determine if increasing type 2 deiodinase (D2) activity in the heart can improve cardiac function and prevent pathological changes.

Main Methods:

• Transient expression of D2 in mouse hearts using the tetracycline transactivator system.
• Analysis of cardiac function, calcium handling, and gene expression under normal and pressure-overload conditions.
• Measurement of cardiac triiodothyronine (T3) levels and D2 activity.

Main Results:

• Increased cardiac D2 activity elevated local T3 levels, enhancing myocardial contractility, Ca(2+) transients, and SR Ca(2+) uptake.
• Phenotypic changes included upregulation of SERCA2a and downregulation of the Na(+)/Ca(2+) exchanger, beta-myosin heavy chain, and SLN.
• In pressure overload, elevated D2 activity prevented impaired contractility and SR Ca(2+) cycling, and normalized altered gene expression, though it did not block hypertrophy.

Conclusions:

• Elevated cardiac D2 activity increases local T3, enhancing myocardial contractility and function.
• Targeting cardiac D2 activity offers a promising strategy to prevent cardiac dysfunction and preserve heart function during stress.
• This approach may overcome limitations of systemic TH therapy by increasing localized active TH (T3) in the heart.