Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, CH-8952 Schlieren, Switzerland.
Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.
Cardiovasc Res. 2021 Mar 21;117(4):1060-1069. doi: 10.1093/cvr/cvaa142.
Fibroblast activation protein (FAP) is upregulated at sites of tissue remodelling including chronic arthritis, solid tumours, and fibrotic hearts. It has also been associated with human coronary atherosclerotic plaques. Yet, the causal role of FAP in atherosclerosis remains unknown. To investigate the cause-effect relationship of endogenous FAP in atherogenesis, we assessed the effects of constitutive Fap deletion on plaque formation in atherosclerosis-prone apolipoprotein E (Apoe) or low-density lipoprotein receptor (Ldlr) knockout mice.
Using en face analyses of thoraco-abdominal aortae and aortic sinus cross-sections, we demonstrate that Fap deficiency decreased plaque formation in two atherosclerotic mouse models (-46% in Apoe and -34% in Ldlr knockout mice). As a surrogate of plaque vulnerability fibrous cap thickness was used; it was increased in Fap-deficient mice, whereas Sirius red staining demonstrated that total collagen content remained unchanged. Using polarized light, atherosclerotic lesions from Fap-deficient mice displayed increased FAP targets in terms of enhanced collagen birefringence in plaques and increased pre-COL3A1 expression in aortic lysates. Analyses of the Stockholm Atherosclerosis Gene Expression data revealed that FAP expression was increased in human atherosclerotic compared to non-atherosclerotic arteries.
Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability with decreased collagen breakdown. Thus, inhibition of FAP expression or activity may not only represent a promising therapeutic target in atherosclerosis but appears safe at the experimental level for FAP-targeted cancer therapies.
成纤维细胞激活蛋白（FAP）在组织重塑部位上调，包括慢性关节炎、实体瘤和纤维化心脏。它也与人类冠状动脉粥样硬化斑块有关。然而，FAP 在动脉粥样硬化中的因果作用尚不清楚。为了研究内源性 FAP 在动脉粥样硬化形成中的因果关系，我们评估了组成型 Fap 缺失对动脉粥样硬化易感载脂蛋白 E（Apoe）或低密度脂蛋白受体（Ldlr）敲除小鼠斑块形成的影响。
通过对胸腹部主动脉和主动脉窦横断面的正面分析，我们证明 Fap 缺乏减少了两种动脉粥样硬化小鼠模型中的斑块形成（Apoe 中的 -46%和 Ldlr 敲除小鼠中的-34%）。作为斑块脆弱性的替代物，使用纤维帽厚度；在 Fap 缺陷小鼠中增加，而天狼星红染色表明总胶原蛋白含量保持不变。使用偏光，Fap 缺陷小鼠的动脉粥样硬化病变显示出增加的 FAP 靶标，表现为斑块中胶原双折射增强和主动脉裂解物中预 COL3A1 表达增加。对斯德哥尔摩动脉粥样硬化基因表达数据的分析表明，与非动脉粥样硬化动脉相比，FAP 在人类动脉粥样硬化中表达增加。
我们的数据提供了因果证据，表明组成型 Fap 缺失可减少实验性动脉粥样硬化的进展，并增加斑块稳定性特征，减少胶原降解。因此，抑制 FAP 表达或活性不仅可能成为动脉粥样硬化的有前途的治疗靶点，而且在实验水平上似乎对 FAP 靶向癌症治疗是安全的。
