Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Department of Cellular and Molecular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Hypertens Res. 2017 Dec;40(12):976-981. doi: 10.1038/hr.2017.73. Epub 2017 Sep 7.
Chymase is an ACE (angiotensin-converting enzyme)-independent angiotensin II-forming enzyme whose expression is increased in the maternal vascular endothelium in preeclampsia. However, mechanisms underlying chymase activation in preeclampsia remain unclear. Cathepsin C is a key enzyme in the activation of several serine proteases including chymase. In this study, we determined whether increased cathepsin C expression/activity might be responsible for the upregulation of chymase expression in preeclampsia. Maternal vascular cathepsin C, chymase and ACE expression were examined through immunohistochemical staining of subcutaneous fat tissue sections of normal and preeclamptic pregnant women. The role of cathepsin C in endothelial chymase and ACE expression was determined in cells treated with cathepsin C. Consequences of chymase activation were then determined by measurement of angiotensin II production in cells treated with the ACE inhibitor captopril and the chymase inhibitor chymostatin, separately and in combination. Expression of both cathepsin C and chymase, but not ACE expression, was markedly increased in the maternal vascular endothelium in subjects with preeclampsia compared with normal pregnant controls. Exogenous cathepsin C induced a dose-dependent increase in expression of mature cathepsin C and chymase, but not ACE, in endothelial cells. Moreover, angiotensin II production was significantly inhibited in cells treated with captopril or chymostatin alone and was further inhibited in cells treated with both inhibitors. These results suggest that cathepsin C upregulation induces chymase activation and subsequently promotes angiotensin II generation in endothelial cells. These data also provide evidence of upregulation of the cathepsin C-chymase-angiotensin signaling axis in maternal vasculature in preeclampsia.
糜酶是一种不依赖于血管紧张素转换酶（ACE）的血管紧张素 II 形成酶，其在子痫前期母体血管内皮中的表达增加。然而，子痫前期中糜酶激活的机制尚不清楚。组织蛋白酶 C 是包括糜酶在内的几种丝氨酸蛋白酶激活的关键酶。在这项研究中，我们确定了组织蛋白酶 C 表达/活性的增加是否可能是导致子痫前期中糜酶表达上调的原因。通过对正常和子痫前期孕妇皮下脂肪组织切片的免疫组织化学染色，检测了母体血管组织蛋白酶 C、糜酶和 ACE 的表达。通过用组织蛋白酶 C 处理细胞，确定了组织蛋白酶 C 在内皮细胞中糜酶和 ACE 表达中的作用。然后通过分别和联合用 ACE 抑制剂卡托普利和糜酶抑制剂糜蛋白酶处理细胞，测量血管紧张素 II 的产生，来确定糜酶激活的后果。与正常妊娠对照组相比，子痫前期患者的母体血管内皮中组织蛋白酶 C 和糜酶的表达明显增加，而 ACE 的表达则没有明显增加。外源性组织蛋白酶 C 诱导内皮细胞中成熟组织蛋白酶 C 和糜酶的表达呈剂量依赖性增加，但 ACE 的表达没有增加。此外，用卡托普利或糜蛋白酶单独处理细胞可显著抑制血管紧张素 II 的产生，而用两种抑制剂联合处理细胞则进一步抑制血管紧张素 II 的产生。这些结果表明，组织蛋白酶 C 的上调诱导了糜酶的激活，进而促进了内皮细胞中血管紧张素 II 的生成。这些数据还提供了证据表明，在子痫前期中，母体血管中组织蛋白酶 C-糜酶-血管紧张素信号轴的表达上调。
