The mechanism of signal transduction during vascular smooth muscle cell proliferation induced by autoantibodies against angiotensin AT1 receptor from hypertension  

作　　者：SUN Yan-xiang ZHANG Hai-yan WEI Yu-miao ZHU Feng WANG Min LIAO Yu-hua 

机构地区：[1]Laboratory of Cardiovascular Immunology, Institute ot Cardiology,Union Hospital, Tongji Medical College of Huazhong Universityof Science and Technology, Wuhan, Hubei 430022, China

出　　处：《Chinese Medical Journal》2008年第1期43-48,共6页中华医学杂志（英文版）

基　　金：The first two authors contributed equally to this work. This study was supported by a grant from National Natural Science Foundation of China （No. G30300/33）.

摘　　要：Background Autoantibodies against angiotensin AT1 receptor have been discovered in patients with preeclampsia or malignant hypertension. Some studies have demonstrated that the autoantibodies are involved in the immunopathogenesis of hypertension and have an agonist effect similar to angiotensin II. Methods Autoantibodies against AT1 receptor were purified from sera of patients with primary hypertension by affinity chromatography. Proliferation of cultured rat vascular smooth muscle cells was detected by bromodeoxyuridine incorporation and activation of signalling molecules detected by Western blotting and electrophoretic mobility shift assay. Results The AT1-RAb caused a significant proliferation similar to the Ang II during first 24 hours. The levels of nuclear factor-KB （NF-KB）, phosphorylated JAK2., phosphorylated STAT1 （pSTAT1） and phosphorylated STAT3 （pSTAT3） molecules were increased in response to the autoantibodies. In contrast, the activations of NF-KB and JAK-STAT were blocked by Iosartan, pyrrolidinedithiocarbamate （a specific inhibitor of NF-KB） and AG490 （a specific inhibitor of the JAK2. tyrosine kinase）. The expressions of NF-KB, pSTAT1 and pSTAT3 reached peak levels at different times. Moreover, the relative densities of electrophoretic bands showed that activation of pSTAT3 was more significant than STAT1 induced by AT1 -RAb. Conclusions These results suggest that the autoantibodies against AT1 receptor have an agonist effect similar to Ang II in proliferation of VSMCs and the NF-KB and JAK-STAT proteins play essential roles. The effect is different from Angll in that STAT3 is the main downstream activating molecule in JAK-STAT signalling pathway.Background Autoantibodies against angiotensin AT1 receptor have been discovered in patients with preeclampsia or malignant hypertension. Some studies have demonstrated that the autoantibodies are involved in the immunopathogenesis of hypertension and have an agonist effect similar to angiotensin II. Methods Autoantibodies against AT1 receptor were purified from sera of patients with primary hypertension by affinity chromatography. Proliferation of cultured rat vascular smooth muscle cells was detected by bromodeoxyuridine incorporation and activation of signalling molecules detected by Western blotting and electrophoretic mobility shift assay. Results The AT1-RAb caused a significant proliferation similar to the Ang II during first 24 hours. The levels of nuclear factor-KB （NF-KB）, phosphorylated JAK2., phosphorylated STAT1 （pSTAT1） and phosphorylated STAT3 （pSTAT3） molecules were increased in response to the autoantibodies. In contrast, the activations of NF-KB and JAK-STAT were blocked by Iosartan, pyrrolidinedithiocarbamate （a specific inhibitor of NF-KB） and AG490 （a specific inhibitor of the JAK2. tyrosine kinase）. The expressions of NF-KB, pSTAT1 and pSTAT3 reached peak levels at different times. Moreover, the relative densities of electrophoretic bands showed that activation of pSTAT3 was more significant than STAT1 induced by AT1 -RAb. Conclusions These results suggest that the autoantibodies against AT1 receptor have an agonist effect similar to Ang II in proliferation of VSMCs and the NF-KB and JAK-STAT proteins play essential roles. The effect is different from Angll in that STAT3 is the main downstream activating molecule in JAK-STAT signalling pathway.

关 键 词：AUTOANTIBODY angiotensin AT1 receptor proliferation Janus kinase-signal transduction activation of transcription nuclear factor-xB 

分 类 号：R542.2[医药卫生—心血管疾病]