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Stress Hormones are Critical in Maintaining Cardiac Gene Expression and Function in Mice

Activation of the hypothalamic–pituitary–adrenal axis results in the release of hormones from the adrenal glands‐ catecholamines, glucocorticoids and mineralocorticoids‐ which function to maintain homeostasis in the face of stressful internal or external challenges. Despite numerous observations suggesting that adrenal hormones exert direct effects on the heart, the molecular mechanisms underlying these actions remain unclear. To understand the biological effects of the stress hormones on the heart, we investigated the impact of loss of endogenous adrenal hormones in mice. Male C57BL/6 mice were adrenalectomized (ADX) at four weeks of age and maintained for 6 months after the surgery to evaluate the effects of long‐term adrenalectomy in cardiac health. We compared heart function and gene expression profiles between intact and ADX mice. Echocardiographic evaluation suggested abnormalities in the left ventricular function with decreased ejection fraction and fractional shortening in ADX mice. Histological evaluation showed an increase in thickness of the left ventricular wall of the ADX mice. Supporting these results electrocardiograms showed that ADX mice presented significantly prolonged QT intervals, indicating that adrenal hormones are important to regulate the electrical activity of the heart. Gene expression analysis of ADX‐hearts revealed an aberrant expression of a large cohort of genes associated with cardiac hypertrophy, arrhythmia and heart failure. Our results indicate that the stress hormones play an essential role in maintaining normal heart function, and suggest that selective modulation of their signaling pathways represent an approach for the treatment of cardiac arrhythmia in humans.