The mechanism of signal transduction during vascular smooth muscle cell proliferation induced by autoantibodies against angiotensin AT1 receptor from hypertension.
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-kappaB (NF-kappaB), phosphorylated JAK2, phosphorylated STAT1 (pSTAT1) and phosphorylated STAT3 (pSTAT3) molecules were increased in response to the autoantibodies. In contrast, the activations of NF-kappaB and JAK-STAT were blocked by losartan, pyrrolidinedithiocarbamate (a specific inhibitor of NF-kappaB) and AG490 (a specific inhibitor of the JAK2 tyrosine kinase). The expressions of NF-kappaB, 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-kappaB and JAK-STAT proteins play essential roles. The effect is different from Ang II in that STAT3 is the main downstream activating molecule in JAK-STAT signalling pathway.
Sun
Yan-xiang
YX
Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
Zhang
Hai-yan
HY
Wei
Yu-miao
YM
Zhu
Feng
F
Wang
Min
M
Liao
Yu-hua
YH
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D049109:Cell Proliferation; D006801:Humans; D006973:Hypertension / Q000276:immunology*; D053614:Janus Kinase 2 / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D016328:NF-kappa B / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D001323:Autoantibodies; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2