Journal
CIRCULATION RESEARCH
Volume 102, Issue 11, Pages 1359-1367Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.174235
Keywords
mineralocorticoid receptor; endothelial cell; aldosterone; spironolactone; ICAM1
Funding
- NHLBI NIH HHS [HL074892, K08 HL074892-01A2, K08 HL074892, R01 HL095590, K08 HL074892-04, K08 HL074892-02, K08 HL074892-03] Funding Source: Medline
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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-beta-hydroxysteroid dehydrogenase-2 (11 beta HSD2), and inhibition of 11 beta HSD2 in aortic ECs enhances gene transactivation by cortisol, supporting that EC 11 beta HSD2 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.
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