Corticosteroid hormone action in cardiomyocytes - impact on heart failure

The adrenal gland is a hormone producing organ that secretes two principal classes of steroid hormones, cortisol and aldosterone. Cortisol through binding to its receptor plays a vitally important role in the body by regulating energy homeostasis, immune function, inflammation and stress response. By contrast, aldosterone by binding to a related receptor regulates salt homeostasis and blood pressure. Besides these effects, many studies have now established that aldosterone exhibits deleterious effects on the heart and blood vessels that may contribute to heart failure in patients with heart disease. Vice versa, medical treatment with drugs that inhibit aldosterone lead to improved survival of patients suffering from heart failure. Cortisol by contrast, seems to play a protective role but the underlying mechanisms are unknown.
Our study aims to determine the specific effects of aldosterone and cortisol on heart muscle cells to clarify the underlying molecular mechanisms that are involved in the development and progression of cardiac disease. Studies will be largely based within the laboratory using cardiac cell lines and heart cells grown from rat heart but will also involve the direct analysis of heart biopsy material from patients undergoing cardiac surgery. A better understanding of these mechanisms will ultimately result in new therapeutic strategies in the treatment of heart failure.

The adrenal produces two corticosteroids, cortisol (glucocorticoid) and aldosterone (mineralocorticoid). Aldosterone plays a central role in blood pressure control by regulating epithelial sodium excretion in the kidney and colon. However, more recently aldosterone action has been linked to cardiovascular pathology. Morphological studies in animals and humans have clearly defined that chronic mineralocorticoid excess leads to cardiac hypertrophy and fibrosis. Moreover, in patients with chronic heart failure circulating aldosterone levels correlate with mortality. The significance of these effects has recently been underpinned by two landmark studies that showed a striking reduction in cardiovascular morbidity and mortality in patients with chronic and acute heart failure treated with small doses of mineralocorticoid receptor antagonists in addition to standard treatment regimens. However, despite these important insights into the detrimental effects of aldosterone on the cardiovascular system we remain completely ignorant of the underlying regulatory molecular mechanisms. In contrast to the kidney where cortisol and aldosterone may mimic each other, depending upon levels of the enzyme 11ßHSD2, cortisol might have opposing effects to aldosterone in the heart. The aim of this proposal is to define the mechanism of corticosteroid hormone action in the heart and to determine whether these involve mineralocorticoid or glucocorticoid pathways. The evaluation of these pathways in cardiac tissue from patients with heart disease should lead to a new understanding of the pathogenesis and treatment of heart failure.