Abstract
Objective Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. Methods and results Apolipoprotein-E (ApoE)−/− mice fed an atherogenic diet and treated with aldosterone for 4 weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE−/−/ICAM-1−/−) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1. Conclusions Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.
| Original language | English |
|---|---|
| Pages (from-to) | 233-242 |
| Number of pages | 10 |
| Journal | International Journal of Cardiology |
| Volume | 232 |
| DOIs | |
| Publication status | Published - Apr 1 2017 |
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Keywords
- Aldosterone
- Atherosclerosis
- Endothelial cells
- Intercellular adhesion molecule-1
- Mineralocorticoid receptor
ASJC Scopus subject areas
- Medicine(all)
- Cardiology and Cardiovascular Medicine
Cite this
Essential role of ICAM-1 in aldosterone-induced atherosclerosis. / Marzolla, Vincenzo; Armani, Andrea; Mammi, Caterina; Moss, Mary E.; Pagliarini, Vittoria; Pontecorvo, Laura; Antelmi, Antonella; Fabbri, Andrea; Rosano, Giuseppe; Jaffe, Iris Z.; Caprio, Massimiliano.
In: International Journal of Cardiology, Vol. 232, 01.04.2017, p. 233-242.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Essential role of ICAM-1 in aldosterone-induced atherosclerosis
AU - Marzolla, Vincenzo
AU - Armani, Andrea
AU - Mammi, Caterina
AU - Moss, Mary E.
AU - Pagliarini, Vittoria
AU - Pontecorvo, Laura
AU - Antelmi, Antonella
AU - Fabbri, Andrea
AU - Rosano, Giuseppe
AU - Jaffe, Iris Z.
AU - Caprio, Massimiliano
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Objective Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. Methods and results Apolipoprotein-E (ApoE)−/− mice fed an atherogenic diet and treated with aldosterone for 4 weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE−/−/ICAM-1−/−) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1. Conclusions Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.
AB - Objective Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. Methods and results Apolipoprotein-E (ApoE)−/− mice fed an atherogenic diet and treated with aldosterone for 4 weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE−/−/ICAM-1−/−) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1. Conclusions Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.
KW - Aldosterone
KW - Atherosclerosis
KW - Endothelial cells
KW - Intercellular adhesion molecule-1
KW - Mineralocorticoid receptor
UR - http://www.scopus.com/inward/record.url?scp=85009495752&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009495752&partnerID=8YFLogxK
U2 - 10.1016/j.ijcard.2017.01.013
DO - 10.1016/j.ijcard.2017.01.013
M3 - Article
AN - SCOPUS:85009495752
VL - 232
SP - 233
EP - 242
JO - International Journal of Cardiology
JF - International Journal of Cardiology
SN - 0167-5273
ER -