Essential role of ICAM-1 in aldosterone-induced atherosclerosis

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.

Impact of adenotonsillectomy on the evolution of inflammatory markers

“…ICAM‐1 mediates T‐cell/T‐cell, T‐cell/target cell and T‐cell/B‐cell interactions in addition to its role in the adhesion of inflammatory cells to the vascular endothelium, which facilitates the endothelial transmigration of leucocytes, an important step in the formation of atheroma plaques. Likewise, the chronic elevation of this molecule can involve a situation linked to cardiovascular risk because of the proatherogenic milieu . Reversing this situation, as can be done after surgery, could be an important preventive factor.…”

“…22 We noted an increase in the values of ICAM-1 in children with because of the proatherogenic milieu. 23 Reversing this situation, as can be done after surgery, could be an important preventive factor.…”

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

“…2008), a necessary step for cardiac leukocyte infiltration and that aldosterone‐induced vascular inflammation in atherosclerosis requires ICAM‐1 (Marzolla et al. 2017). Moreover, we and others have recently demonstrated that ICAM‐1 is necessary for T‐cell recruitment to the heart (Salvador et al.…”

“…2013; Marzolla et al. 2017). We recently showed using the TAC model, that ICAM‐1 is necessary for recruitment of T cells and proinflammatory monocytes to the heart in response to pressure overload and that this mechanism is necessary for progression to systolic dysfunction and HF (Nevers et al.…”

Vascular and inflammatory mineralocorticoid receptors in kidney disease

“…9,10 The vascular inflammation documented after MR activation in the endothelium is associated with increased expression of the adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) 11 and vascular cell adhesion molecule 1 (VCAM-1). 13 The increased expression of adhesion molecules may facilitate leucocyte infiltration, thus amplifying the inflammatory response in the kidney. 13 The increased expression of adhesion molecules may facilitate leucocyte infiltration, thus amplifying the inflammatory response in the kidney.…”