Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian, Medical University, Dalian, China.
Am J Physiol Heart Circ Physiol. 2019 Dec 1;317(6):H1301-H1311. doi: 10.1152/ajpheart.00566.2019. Epub 2019 Nov 15.
Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like superfamily of adhesion molecules that mediate leukocyte adhesion to vascular endothelium and are involved in several cardiovascular diseases, including ischemia-reperfusion injury, myocardial infarction, and atherosclerosis. However, the role of ICAM-1 in angiotensin II (ANG II)-induced cardiac remodeling in mice remains unclear. Wild-type mice were administered an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and ANG II (1,000 ng·kg·min) for up to 14 days. Cardiac contractile function and structure were detected by echocardiography. Hypertrophy, fibrosis, and inflammation were assessed by histological examination. The infiltration of lymphocyte function-associated antigen-1 (LFA-1) monocytes/macrophages was assessed by immunostaining. The mRNA expression of genes was evaluated by quantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We found that ICAM-1 expression in ANG II-infused hearts and ICAM-1 levels in serum from human patients with heart failure were significantly increased. Moreover, ANG II infusion markedly enhanced ANG II-induced hypertension, caused cardiac contractile dysfunction, and promoted cardiac hypertrophy, fibrosis, and LFA-1 macrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing antibody dose-dependently attenuated these effects. Moreover, our in vitro data further demonstrated that blocking ICAM-1 inhibited ANG II-induced LFA-1 macrophage adhesion to endothelial cells and migration. In conclusion, these results provide novel evidence that blocking ICAM-1 exerts a protective effect in ANG II-induced cardiac remodeling at least in part through the modulation of adhesion and infiltration of LFA-1 macrophages in the heart. Inhibition of ICAM-1 may represent a new therapeutic approach for hypertrophic heart diseases. Leukocyte adhesion to vascular endothelium is a critical step in cardiovascular diseases. ICAM-1 is a member of immunoglobulin-like superfamily of adhesion molecules that binds LFA-1 to mediate leukocytes adhesion and migration. However, the significance of ICAM-1 in ANG II-induced cardiac remodeling remains unclear. This study reveals that blocking of ICAM-1 prevents ANG II-induced cardiac remodeling via modulating adhesion and migration of LFA-1 monocytes, may serve as a novel therapeutic target for hypertensive cardiac diseases.
细胞间黏附分子-1（ICAM-1）是免疫球蛋白超家族黏附分子的成员之一，介导白细胞与血管内皮的黏附，并参与多种心血管疾病，包括缺血再灌注损伤、心肌梗死和动脉粥样硬化。然而，ICAM-1 在血管紧张素 II（ANG II）诱导的小鼠心脏重构中的作用尚不清楚。野生型小鼠分别给予 IgG 对照或 ICAM-1 中和抗体（1 和 2 mg/只）和 ANG II（1000 ng·kg·min），持续 14 天。通过超声心动图检测心脏收缩功能和结构。通过组织学检查评估肥大、纤维化和炎症。通过免疫染色评估淋巴细胞功能相关抗原-1（LFA-1）单核细胞/巨噬细胞的浸润。通过定量 RT-PCR 分析评估基因的 mRNA 表达。通过免疫印迹法检测蛋白水平。我们发现，ANG II 输注心脏中 ICAM-1 的表达和心力衰竭患者血清中 ICAM-1 的水平显著增加。此外，ANG II 输注显著增强了 ANG II 诱导的高血压，导致心脏收缩功能障碍，并促进了心脏肥大、纤维化和 LFA-1 巨噬细胞浸润。相反，用中和抗体阻断 ICAM-1 呈剂量依赖性减弱了这些作用。此外，我们的体外数据进一步表明，阻断 ICAM-1 抑制了 ANG II 诱导的 LFA-1 巨噬细胞黏附内皮细胞和迁移。总之，这些结果提供了新的证据，表明阻断 ICAM-1 至少部分通过调节心脏中 LFA-1 巨噬细胞的黏附和浸润，在 ANG II 诱导的心脏重构中发挥保护作用。抑制 ICAM-1 可能为肥厚性心脏病提供一种新的治疗方法。白细胞与血管内皮的黏附是心血管疾病的关键步骤。ICAM-1 是免疫球蛋白超家族黏附分子的成员，通过结合 LFA-1 介导白细胞黏附和迁移。然而，ICAM-1 在 ANG II 诱导的心脏重构中的意义尚不清楚。这项研究表明，阻断 ICAM-1 通过调节 LFA-1 单核细胞的黏附和迁移来预防 ANG II 诱导的心脏重构，可能成为高血压性心脏病的新治疗靶点。
