Thyroid hormone receptor function in maturing ovine cardiomyocytes.

Area of Science:

• Cardiovascular Physiology
• Endocrinology
• Developmental Biology

Background:

• Plasma tri-iodo-l-thyronine (T3) increases late in gestation, inhibiting cardiomyocyte proliferation and promoting maturation.
• Thyroid hormone receptors (TRs) mediate T3's actions in fetal cardiomyocytes, with TRα1 and TRβ1 expression increasing with age.

Purpose of the Study:

• To investigate whether T3-induced changes in fetal ovine cardiomyocytes are mediated via TRs or non-genomic mechanisms.
• To assess the role of TRα1/α2 in T3 signaling pathways like ERK and Akt.

Main Methods:

• Primary fetal ovine cardiomyocytes were isolated at 102 and 135 days of gestational age.
• Cells were treated with T3, IGF-1, a TR antagonist (NH3), or TRα1/α2 siRNA.
• Proliferation was measured by BrdU uptake; protein levels (ERK, Akt, TRs, p21) were assessed via Western blot.

Main Results:

• TRα1 protein levels were consistently higher than TRβ1 in ovine fetal hearts.
• T3 reduced IGF-1-stimulated proliferation, an effect blocked by NH3 or TRα1/α2 knockdown.
• TR blockade and knockdown affected ERK and Akt signaling, with age-dependent sensitivity.

Conclusions:

• TRs are crucial for normal proliferation and T3 signaling in fetal ovine cardiomyocytes.
• The sensitivity of cardiomyocytes to TR blockade is dependent on gestational age.
• Genomic actions of TRs, not non-genomic mechanisms, mediate T3's effects on proliferation.