Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
J Am Coll Cardiol. 2011 Jan 4;57(1):99-109. doi: 10.1016/j.jacc.2010.07.035.
We investigated the effects of human resistin on atherosclerotic progression and clarified its underlying mechanisms.
Resistin is an adipokine first identified as a mediator of insulin resistance in murine obesity models. But, its role in human pathology is under debate. Although a few recent studies suggested the relationship between resistin and atherosclerosis in humans, the causal relationship and underlying mechanism have not been clarified.
We cloned rabbit resistin, which showed 78% identity to human resistin at the complementary deoxyribonucleic acid level, and its expression was examined in 3 different atherosclerotic rabbit models. To evaluate direct role of resistin on atherosclerosis, collared rabbit carotid arteries were used. Histological and cell biologic analyses were performed.
Rabbit resistin was expressed by macrophages of the plaque in the 3 different atherosclerotic models. Peri-adventitial resistin gene transfer induced macrophage infiltration and expression of various inflammatory cytokines, resulting in the acceleration of plaque growth and destabilization. In vitro experiments elucidated that resistin increased monocyte-endothelial cell adhesion by upregulating very late antigen-4 on monocytes and their counterpart vascular cell adhesion molecule-1 on endothelial cells. Resistin augmented monocyte infiltration in collagen by direct chemoattractive effect as well as by enhancing migration toward monocyte chemotactic protein-1. Administration of connecting segment-1 peptide, which blocks very late antigen-4 × vascular cell adhesion molecule-1 interaction, ameliorated neointimal growth induced by resistin in vivo.
Our results indicate that resistin aggravates atherosclerosis by stimulating monocytes, endothelial cells, and vascular smooth muscle cells to induce vascular inflammation. These findings provide the first insight on the causal relationship between resistin and atherosclerosis.
我们研究了人抵抗素对动脉粥样硬化进展的影响，并阐明了其潜在机制。
抵抗素最初作为肥胖啮齿动物模型中胰岛素抵抗的介质被鉴定为一种脂肪细胞因子。然而，其在人体病理学中的作用仍存在争议。尽管最近的一些研究表明抵抗素与人类动脉粥样硬化之间存在一定关系，但因果关系和潜在机制尚未阐明。
我们克隆了兔抵抗素，其与人类抵抗素在互补 DNA 水平上具有 78%的同源性，并在 3 种不同的动脉粥样硬化兔模型中检测了其表达情况。为了评估抵抗素对动脉粥样硬化的直接作用，我们使用了套圈兔颈动脉。进行了组织学和细胞生物学分析。
兔抵抗素在 3 种不同的动脉粥样硬化模型中的斑块巨噬细胞中表达。斑块周围的抵抗素基因转移诱导了巨噬细胞浸润和各种炎症细胞因子的表达，导致斑块生长加速和不稳定性增加。体外实验阐明了抵抗素通过上调单核细胞上的非常晚期抗原-4 和内皮细胞上的其对应血管细胞黏附分子-1，增加单核细胞-内皮细胞黏附，从而促进单核细胞浸润。抵抗素通过直接趋化作用以及增强对单核细胞趋化蛋白-1的迁移，增强了胶原内单核细胞的浸润。连接段-1 肽的给药，该肽可阻断非常晚期抗原-4×血管细胞黏附分子-1 相互作用，改善了抵抗素在体内诱导的新生内膜增生。
我们的研究结果表明，抵抗素通过刺激单核细胞、内皮细胞和血管平滑肌细胞，诱导血管炎症，从而加重动脉粥样硬化。这些发现为抵抗素与动脉粥样硬化之间的因果关系提供了首次见解。
