Conditional glucocorticoid receptor expression in the heart induces atrio-ventricular block

Area of Science:

• Cardiovascular Pathophysiology
• Endocrinology
• Molecular Cardiology

Background:

• Corticosteroid hormones, including glucocorticoids (GCs), modulate cardiovascular health, but their precise cardiac roles are unclear.
• GCs, widely used therapeutically, can cause adverse cardiovascular effects like heart failure and hypertension.
• Direct cardiac effects of GCs are challenging to study due to widespread glucocorticoid receptor (GR) expression.

Purpose of the Study:

• To investigate the direct effects of glucocorticoid receptor (GR) on cardiac function.
• To elucidate the specific roles of GR in cardiomyocyte pathophysiology using a conditional mouse model.

Main Methods:

• Developed a conditional transgenic mouse model with cardiomyocyte-specific GR overexpression.
• Assessed cardiac function via electrocardiogram (ECG) and isolated ventricular cardiomyocyte electrophysiology.
• Evaluated ion channel activity, calcium homeostasis, and cardiac structure (hypertrophy, fibrosis).

Main Results:

• Transgenic mice exhibited significant ECG abnormalities, including prolonged PQ, QRS, and QTc intervals, and atrio-ventricular block.
• Cardiomyocytes showed altered ion channel function (reduced I(Na), I(to), I(Kslow)) and impaired calcium handling.
• ECG abnormalities were reversible upon GR expression suppression, and no cardiac hypertrophy or fibrosis was observed.

Conclusions:

• GR activation has direct and specific detrimental effects on cardiac electrophysiology.
• GR influences cardiomyocyte ion channel function and calcium homeostasis, leading to ECG alterations.
• This study provides novel insights into the direct cardiac impact of GR, distinct from mineralocorticoid receptor effects.