Marzolla Vincenzo, Armani Andrea, Mammi Caterina, Moss Mary E, Pagliarini Vittoria, Pontecorvo Laura, Antelmi Antonella, Fabbri Andrea, Rosano Giuseppe, Jaffe Iris Z, Caprio Massimiliano
Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy.
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA.
Int J Cardiol. 2017 Apr 1;232:233-242. doi: 10.1016/j.ijcard.2017.01.013. Epub 2017 Jan 5.
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.
Apolipoprotein-E (ApoE) mice fed an atherogenic diet and treated with aldosterone for 4weeks 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.
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.
醛固酮水平升高与动脉粥样硬化并发症风险增加相关，而使用盐皮质激素受体（MR）拮抗剂进行治疗可降低心血管事件的发生率。在此，我们检验醛固酮通过调节细胞间黏附分子-1（ICAM-1）表达促进早期动脉粥样硬化的假说，并研究醛固酮调节ICAM-1表达的分子机制。
喂食致动脉粥样硬化饮食并接受醛固酮治疗4周的载脂蛋白E（ApoE）小鼠，其血管ICAM-1表达增加，同时主动脉根部动脉粥样硬化斑块大小增大。此外，醛固酮治疗导致斑块脂质和炎症细胞含量增加，与不稳定斑块表型一致。ApoE/ICAM-1双敲除（ApoE/ICAM-1）同窝小鼠免受醛固酮诱导的斑块大小、脂质含量和巨噬细胞浸润增加的影响。由于已知醛固酮在人内皮细胞中通过MR调节ICAM-1转录，我们探索了MR对ICAM-1启动子的调节作用。在人脐静脉内皮细胞（HUVECs）中使用人ICAM-1基因启动子的缺失构建体进行的荧光素酶报告基因测定表明，包含预测的MR反应元件（MRE）的区域是MR依赖的ICAM-1转录调节所必需的。
醛固酮的促动脉粥样硬化作用是通过增加ICAM-1表达介导的，这是通过内皮MR的转录调节实现的。这些数据加深了我们对MR激活促进动脉粥样硬化并发症分子机制的理解。
