Published online before print May 8, 2008, doi: 10.1161/CIRCRESAHA.108.174235
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Submitted on August 9, 2007
Revised on April 22, 2008
Accepted on April 24, 2008
Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate Intercellular Adhesion Molecule-1 Expression and Promote Leukocyte Adhesion
Massimiliano Caprio ;
From the Molecular Cardiology Research Institute (B.G.N., W.B., M.E.M., I.Z.J.), Department of Medicine-Division of Cardiology, Tufts Medical Center and Tufts University School of Medicine, Boston, Mass; Istituto di Ricovero e Cura a Carattere Scientifico (M.C., A.l.S., G.R.), San Raffaele Pisana, Rome, Italy; and Unit of Endocrinology (M.C., A.F.), Ospedale Sant'Eugenio, Departement of Internal Medicine, University Tor Vergata, Rome, Italy.
* To whom correspondence should be addressed. E-mail: ijaffe{at}tuftsmedicalcenter.org.
In clinical trials, aldosterone antagonists decrease cardiovascular mortality and ischemia by unknown mechanisms. The steroid hormone aldosterone acts by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor. In humans, aldosterone causes MR-dependent endothelial cell (EC) dysfunction and in animal models, aldosterone increases vascular macrophage infiltration and atherosclerosis. MR antagonists inhibit these effects without changing blood pressure, suggesting a direct role for vascular MR in EC function and atherosclerosis. Whether human vascular ECs express functional MR is not known. Here, we show that human coronary artery and aortic ECs express MR mRNA and protein and that EC MR mediates aldosterone-dependent gene transcription. Human ECs also express the enzyme 11-
-hydroxysteroid dehydrogenase-2 (11HSD2), and inhibition of 11HSD2 in aortic ECs enhances gene transactivation by cortisol, supporting that EC 11HSD2 is functional. Furthermore, aldosterone stimulates transcription of the proatherogenic leukocyte–EC adhesion molecule intercellular adhesion molecule (ICAM)1 gene and protein expression on human coronary artery ECs, an effect inhibited by the MR antagonist spironolactone and by MR knock down with small interfering RNA. Cell adhesion assays demonstrate that aldosterone promotes leukocyte–EC adhesion, an effect that is inhibited by spironolactone and ICAM1 blocking antibody, supporting that aldosterone induction of EC ICAM1 surface expression via MR mediates leukocyte–EC adhesion. These data show that aldosterone activates endogenous EC MR and proatherogenic gene expression in clinically important human ECs. These studies describe a novel mechanism by which aldosterone may influence ischemic cardiovascular events and support a new explanation for the decrease in ischemic events in patients treated with aldosterone antagonists.
Key words: mineralocorticoid receptor • endothelial cell • aldosterone • spironolactone • ICAM1
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