Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
Circ Res. 2011 May 27;108(11):1316-27. doi: 10.1161/CIRCRESAHA.111.243758. Epub 2011 Apr 14.
Mast cells (MCs) contribute to the formation of abdominal aortic aneurysms (AAAs) by producing biologically active mediators. Tryptase is the most abundant MC granule protein and participates in MC activation, protease maturation, leukocyte recruitment, and angiogenesis-all processes critical to AAA pathogenesis.
To test the hypothesis that tryptase participates directly in AAA formation.
Immunohistochemistry demonstrated enhanced tryptase staining in media and adventitia of human and mouse AAA lesions. Serum tryptase levels correlated significantly with the annual expansion rate of AAA before (r = 0.30, P = 0.003) and after (r = 0.29, P = 0.005) adjustment for common AAA risk factors in a patient follow-up study, and associated with risks for later surgical repair or overall mortality before (P = 0.009, P = 0.065) and after (P = 0.004, P = 0.001) the adjustment. Using MC protease-6-deficient mice (Mcpt6(-/-)) and aortic elastase perfusion-induced experimental AAAs, we proved a direct role of this tryptase in AAA pathogenesis. Whereas all wild-type (WT) mice developed AAA at 14 or 56 days postperfusion, Mcpt6(-/-) mice were fully protected. AAA lesions from Mcpt6(-/-) mice had fewer inflammatory and apoptotic cells, and lower chemokine levels, than did those from WT mice. MC from WT mice restored reduced AAA lesions and lesion inflammatory cell content in MC-deficient Kit(W-sh/W-sh) mice, but those prepared from Mcpt6(-/-) mice did not. Mechanistic studies demonstrated that tryptase deficiency affected endothelial cell (EC) chemokine and cytokine expression, monocyte transmigration, smooth-muscle cell apoptosis, and MC and AAA lesion cysteinyl cathepsin expression and activities.
This study establishes the direct participation of MC tryptase in the pathogenesis of experimental AAAs, and suggests that levels of this protease can serve as a novel biomarker for abdominal aortic expansion.
肥大细胞（MCs）通过产生生物活性介质促进腹主动脉瘤（AAA）的形成。类胰蛋白酶是 MC 颗粒中含量最丰富的蛋白，参与 MC 激活、蛋白酶成熟、白细胞募集和血管生成——所有这些过程都是 AAA 发病机制的关键。
验证类胰蛋白酶直接参与 AAA 形成的假说。
免疫组织化学显示，人及鼠 AAA 病变的中膜和外膜中增强的类胰蛋白酶染色。在一项患者随访研究中，血清类胰蛋白酶水平与 AAA 的年扩张率显著相关，在调整常见 AAA 危险因素之前（r = 0.30，P = 0.003）和之后（r = 0.29，P = 0.005）均相关，并且与随访期间的手术修复或总死亡率风险相关，在调整之前（P = 0.009，P = 0.065）和之后（P = 0.004，P = 0.001）均相关。通过使用 MC 蛋白酶-6 缺陷型（Mcpt6(-/-)）小鼠和主动脉弹性蛋白酶灌注诱导的实验性 AAA，我们证明了这种类胰蛋白酶在 AAA 发病机制中的直接作用。尽管所有野生型（WT）小鼠在灌注后 14 或 56 天均发生 AAA，但 Mcpt6(-/-) 小鼠完全得到保护。Mcpt6(-/-) 小鼠的 AAA 病变中炎症细胞和凋亡细胞较少，趋化因子水平较低，而 WT 小鼠的病变则较多。来自 WT 小鼠的 MC 可恢复 MC 缺陷型 Kit(W-sh/W-sh) 小鼠中减轻的 AAA 病变和病变炎症细胞含量，但来自 Mcpt6(-/-) 小鼠的 MC 则不能。机制研究表明，类胰蛋白酶缺陷影响内皮细胞（EC）趋化因子和细胞因子表达、单核细胞迁移、平滑肌细胞凋亡以及 MC 和 AAA 病变半胱氨酸组织蛋白酶表达和活性。
本研究确立了 MC 类胰蛋白酶在实验性 AAA 发病机制中的直接参与，并提示该蛋白酶水平可作为腹主动脉扩张的新型生物标志物。
