Hammer, Fabian (2011)
Ph.D. thesis, University of Birmingham.
The cardiovascular system (CVS) has emerged as an important target of corticosteroid hormones. Mineralocorticoid receptor antagonists provide cardiovascular protection and are now routinely used in disorders such as primary hyperaldosteronism, resistant hypertension and congestive heart failure (CHF) but the underlying molecular mechanisms of corticosteroid hormone action remain unclear. We have characterised corticosteroid hormone action and metabolism by 11β- hydroxysteroid-dehydrogenases (11β-HSDs) in isolated adult rat cardiomyocytes (CM) and cardiac fibroblasts (cFb). We have detected 11β-HSD1 expression and activity in CM and cFb where it facilitates glucocorticoid hormone action, whereas 11β-HSD2 was absent. We have shown differential gene regulation by aldosterone (Aldo) and corticosterone in CM and identified novel Aldo target genes which may provide insights into the molecular mechanisms of Aldo action. We have also studied the role of corticosteroids in essential hypertension and the effect of spironolactone (Spiro) upon their secretion and metabolism in patients with chronic kidney disease. We have shown that mineralocorticoids but not glucocorticoids are involved in elevated blood pressure in essential hypertension and that Spiro treatment results in compensatory activation of the renin-angiotensinaldosterone system (RAAS), whereas glucocorticoid secretion and metabolism remain unchanged. In summary, these data provide novel molecular and clinical insights into corticosteroid hormone action in the CVS.
|Type of Work:||Ph.D. thesis.|
|Supervisor(s):||Stewart, Paul M|
|School/Faculty:||Colleges (2008 onwards) > College of Medical & Dental Sciences|
|Department:||School of Clinical and Experimental Medicine|
|Subjects:||R Medicine (General)|
RC Internal medicine
|Institution:||University of Birmingham|
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