Department for Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.
EMBO Mol Med. 2012 Jul;4(7):564-76. doi: 10.1002/emmm.201200237. Epub 2012 Apr 19.
Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion.
动脉粥样硬化病变是动脉内膜的非对称局灶性增厚，由脂质、各种细胞类型和细胞外基质 (ECM) 组成。这些病变导致血管阻塞，是西方世界最常见的死亡原因。血管阻塞的主要原因是动脉粥样硬化病变破裂，随后形成血栓。纤连蛋白 (FN) 是最早沉积在易发生动脉粥样硬化部位的 ECM 蛋白之一，被认为可促进动脉粥样硬化病变的形成。在这里，我们报告载脂蛋白 E 基因敲除小鼠缺乏肝细胞衍生的血浆 FN (pFN)，易发生动脉粥样硬化，喂食致动脉粥样硬化饮食后，易发生动脉粥样硬化部位的 FN 沉积明显减少，导致动脉粥样硬化斑块明显变小、数量减少。然而，pFN 缺陷小鼠的动脉粥样硬化病变缺乏血管平滑肌细胞，无法形成纤维帽。因此，我们的结果表明，尽管 FN 通过增加致动脉粥样硬化斑块面积使动脉粥样硬化恶化，但它促进了保护性纤维帽的形成，在人类中，纤维帽可防止斑块破裂和血管阻塞。
