期刊
REGULATORY PEPTIDES
卷 185, 期 -, 页码 44-51出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.regpep.2013.06.007
关键词
Angiotensin-converting enzyme 2; Angiotensin II; Suppressor of cytokine signaling 3; Profilin-1; Oxidative stress; Cell proliferation
资金
- National Natural Science Foundation of China [81170246, 30973522, 81273599, 81270801]
- Shanghai Pujiang Talents Program of Shanghai Science and Technology Committee [11PJ1408300]
- Scientific Research Project of Health Bureau of Shanghai [2011347]
- Canadian Institute for Health Research [86602]
Angiotensin (Ang) II plays a vital role in vascular smooth muscle cell (VSMC) growth and proliferation. Angiotensin-converting enzyme 2 (ACE2) is a specific Ang II-degrading enzyme but its role in VSMC proliferation remains largely unknown. We hypothesized that ACE2 might suppress Ang II-mediated oxidative stress and VSMC proliferation. Human umbilical artery smooth muscle cells (HUASMCs) were pretreated with Ang II (100 nM) for 6 h and 24 h, respectively. Exposure to Ang II resulted in significant increases in suppressor of cytokine signaling 3 (SOCS3) expression and phosphorylation levels of JAK2, STAT3 and ERK1/2 linked with elevated superoxide production and cell proliferation in HUASMCs. These changes were strikingly prevented by administration of ERK1/2 inhibitor PD98059 (10 mu M) and JAK/STAT inhibitor WP1066 (5 mu M) but were largely aggravated by ACE2 inhibitor DX600 (0.5 mu M). More importantly, treatment with human recombinant ACE2 (hrACE2; 1 mg/ml) dramatically prevented Ang II-mediated SOCS3 expression and the JAK2-STAT3 and ERK1/2 signaling, and resulted in attenuation of superoxide production and cell proliferation in HUASMCs. Intriguingly, downregulation of profilin-1 with profilin-1 siRNA (50 nM) was able to abolish Ang II-induced upregulations of profilin-1 expression, ERK1/2 phosphorylation and superoxide production with attenuation of VSMC proliferation. In conclusion, treatment with hrACE2 prevents Ang II-mediated activation of the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways, contributing to attenuation of superoxide generation and cell proliferation in HUASMCs, suggesting a protective mechanism of ACE2 against Ang II-mediated oxidative stress and VSMC proliferation. ACE2 may represent a potential candidate to prevent and treat vascular disorders. (C) 2013 Elsevier B.V. All rights reserved.
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