ECE2020 Audio ePoster Presentations Hot topics (including COVID-19) (110 abstracts)
Intact endothelial epoxyeicosatrienoic acids pathway in primary aldosteronism – the route to new treatment strategies?
Laura Fruehbuss 1 , Yao Meng 1 , Jing Sun 1 , Jair Gonzalez Marques 2 , Berthold Koletzko 2 , Michael Mederos Y Schnitzler 3 , Thomas Gudermann 3 , Felix Beuschlein 1,4 , Tracy Ann Williams 1,5 , Daniel Heinrich 1 , Christian Adolf 1 , Martin Reincke 1 & Holger Schneider 1
1Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, München, Germany; 2Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, Klinikum der Universität München, LMU München, München, Germany; 3Walther-Straub-Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, LMU München, München, Germany; 4Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland; 5Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Turin, Turin, Italy
Rationale: Endothelial dysfunction (ED) is a hallmark of primary aldosteronism and paves the way for subsequent atherosclerotic disease. Past research has confirmed that one factor involved in ED is disturbed nitric oxide (NO) signalling. Since defects in NO release alone cannot explain the whole effect, we set out to address the role of endothelial CYP-expoygenase products (epoxyeicosatrienoic acids, EETs) in aldosterone-mediated endothelial dysfunction.
Objective: Todelineate aldosterone-mediated changes in expression patterns of critical genes which are necessary for the generation of EETs in endothelial cells and their action in smooth muscle cells;to assess stimulated EET release from endothelial cells after chronic aldosterone excess; and tomeasure smooth muscle calcium response to EETs after chronic aldosterone excess. To account for potential co-stimulation of mineralocorticoid receptors, are exposed to physiological levels of cortisol and pathologically relevant levels of aldosterone in parallel.
Methods and results: We show with qPCR and western blot that aldosterone excess in primary human coronary artery endothelial and smooth muscle cells does not change the expression of relevant enzymes (CYPepoxygenases, epoxide hydrolases) and channels which are deemed to be vital for an effective EET pathway. We further demonstrate BKCa channels to be mostly downregulated by physiological levels of glucocorticoids in a glucocorticoid receptor-dependent manner. Aldosterone at concentrations found in patients with primary aldosteronism (1 nM) had only minor impact on BKCa expression. Moreover, we found that stimulated endothelial EET release was unaffected by aldosterone excess. Aldosterone likewise did not induce changes in smooth muscle cell calcium transients to 14,15 EET.
Conclusions: This first systematic investigation of the EET pathway in the context of aldosterone excess demonstrates that neither the endothelial release of nor the smooth muscle response to EETs is seemingly affected by aldosterone excess. Clinical trials aiming to increase the concentration of EETs by inhibiting their breakdown are thus very likely to be effective. We also disentangle the relationship between mineralo- and glucocorticoids on BKCa channel expression. These findings have potential implications for conditions of endogenous or iatrogenic glucocorticoid excess as well as glucocorticoid co-secretion in primary aldosteronism.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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