From the Department of Physiology (M.S., M.H., Z.K.).
Faculty of Medicine and Dentistry (M.S., M.H., G.Y.O., Z.K.).
Circ Res. 2018 Jul 20;123(3):372-388. doi: 10.1161/CIRCRESAHA.118.313181. Epub 2018 Jun 21.
ADAM17 (a disintegrin and metalloproteinase-17) is a membrane-bound enzyme that regulates bioavailability of multiple transmembrane proteins by proteolytic processing. ADAM17 has been linked to several pathologies, but its role in thoracic aortic aneurysm (TAA) has not been determined.
The objective of this study was to explore the cell-specific functions of vascular ADAM17 in the pathogenesis and progression of TAA.
In aneurysmal thoracic aorta from patients, ADAM17 was increased in tunica media and intima. To determine the function of ADAM17 in the major cells types within these regions, we generated mice lacking ADAM17 in smooth muscle cells (SMC; ) or endothelial cells ( ). ADAM17 deficiency in either cell type was sufficient to suppress TAA dilation markedly and adverse remodeling in males and females (in vivo) although through different mechanisms. ADAM17 deficiency in SMCs prevented the contractile-to-synthetic phenotypic switching in these cells after TAA induction, preventing perivascular fibrosis, inflammation, and adverse aortic remodeling. Loss of ADAM17 in endothelial cells protected the integrity of the intimal barrier by preserving the adherens junction (vascular endothelial-cadherin) and tight junctions (junctional adhesion molecule-A and claudin). In vitro studies on primary mouse thoracic SMCs and human primary aortic SMCs and endothelial cells (± small interfering RNA) confirmed the cell-specific functions of ADAM17 and demonstrated the cross-species validity of these findings. To determine the impact of ADAM17 inhibition in treating TAA, we used an ADAM17-selective inhibitor (PF-548) before or 3 days after TAA induction. In both cases, ADAM17 inhibition prevented progression of aneurysmal growth.
We have identified distinct cell-specific functions of ADAM17 in TAA progression, promoting pathological remodeling of SMC and impairing integrity of the intimal endothelial cell barrier. The dual impact of ADAM17 deficiency (or inhibition) in protecting 2 major cell types in the aortic wall highlights the unique position of this proteinase as a critical treatment target for TAA.
ADAM17（解整合素金属蛋白酶 17）是一种膜结合酶，通过蛋白水解作用调节多种跨膜蛋白的生物利用度。ADAM17 与多种病理有关，但它在胸主动脉瘤（TAA）中的作用尚未确定。
本研究旨在探讨血管 ADAM17 在 TAA 发病机制和进展中的细胞特异性功能。
在患者的胸主动脉瘤中，ADAM17 在中膜和内膜中增加。为了确定 ADAM17 在这些区域主要细胞类型中的功能，我们生成了血管平滑肌细胞（SMC； ）或内皮细胞（ ）中缺乏 ADAM17 的小鼠。ADAM17 在任一种细胞类型中的缺失足以显著抑制雄性和雌性（体内）TAA 扩张和不良重塑，尽管其机制不同。SMC 中 ADAM17 的缺失可防止这些细胞在 TAA 诱导后的收缩型到合成型表型转换，防止血管周围纤维化、炎症和不良的主动脉重塑。内皮细胞中 ADAM17 的缺失通过维持黏附连接（血管内皮钙黏蛋白）和紧密连接（连接黏附分子-A 和闭合蛋白）来保护内膜屏障的完整性。对原代小鼠胸主动脉 SMC 和人原代主动脉 SMC 和内皮细胞（±小干扰 RNA）的体外研究证实了 ADAM17 的细胞特异性功能，并证明了这些发现的跨物种有效性。为了确定 ADAM17 抑制在治疗 TAA 中的作用，我们在 TAA 诱导前或 3 天后使用 ADAM17 选择性抑制剂（PF-548）。在这两种情况下，ADAM17 抑制均可阻止动脉瘤生长的进展。
我们已经确定了 ADAM17 在 TAA 进展中具有独特的细胞特异性功能，促进了 SMC 的病理性重塑，并损害了内膜内皮细胞屏障的完整性。ADAM17 缺乏（或抑制）对主动脉壁中 2 种主要细胞类型的双重影响突显了这种蛋白酶作为 TAA 关键治疗靶点的独特地位。
