Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
The second Clinical Medical School of Inner Mongolia University for Nationalities, Inner Mongolia Forestry General Hospital, Inner Mongolia, China.
Sci Rep. 2016 Nov 23;6:37635. doi: 10.1038/srep37635.
Although increases in cardiovascular load (pressure overload) are known to elicit ventricular remodeling including cardiomyocyte hypertrophy and interstitial fibrosis, the molecular mechanisms of pressure overload or AngII -induced cardiac interstitial fibrosis remain elusive. In this study, serpinE2/protease nexin-1 was over-expressed in a cardiac fibrosis model induced by pressure-overloaded via transverse aortic constriction (TAC) in mouse. Knockdown of serpinE2 attenuates cardiac fibrosis in a mouse model of TAC. At meantime, the results showed that serpinE2 significantly were increased with collagen accumulations induced by AngII or TGF-β stimulation in vitro. Intriguingly, extracellular collagen in myocardial fibroblast was reduced by knockdown of serpinE2 compared with the control in vitro. In stark contrast, the addition of exogenous PN-1 up-regulated the content of collagen in myocardial fibroblast. The MEK1/2- ERK1/2 signaling probably promoted the expression of serpinE2 via transcription factors Elk1 in myocardial fibroblast. In conclusion, stress-induced the ERK1/2 signaling pathway activation up-regulated serpinE2 expression, consequently led accumulation of collagen protein, and contributed to cardiac fibrosis.
虽然已知心血管负荷（压力超负荷）的增加会引起心室重构，包括心肌细胞肥大和间质纤维化，但压力超负荷或 AngII 诱导的心脏间质纤维化的分子机制仍不清楚。在这项研究中，丝氨酸蛋白酶抑制剂 E2/蛋白酶神经素-1（serpinE2/protease nexin-1）在通过横主动脉缩窄（TAC）诱导的心脏纤维化模型中过表达。在 TAC 小鼠模型中，serpinE2 的敲低可减轻心脏纤维化。同时，结果表明，在体外，丝氨酸蛋白酶抑制剂 E2 随着 AngII 或 TGF-β刺激诱导的胶原积累而显著增加。有趣的是，与体外对照相比，敲低丝氨酸蛋白酶抑制剂 E2 可减少心肌成纤维细胞中的细胞外胶原。相比之下，外源性 PN-1 的添加可上调心肌成纤维细胞中胶原的含量。MEK1/2-ERK1/2 信号通路可能通过心肌成纤维细胞中的转录因子 Elk1 促进丝氨酸蛋白酶抑制剂 E2 的表达。总之，应激诱导的 ERK1/2 信号通路激活上调丝氨酸蛋白酶抑制剂 E2 的表达，进而导致胶原蛋白的积累，并导致心脏纤维化。
