Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways

Abstract

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 (100nM) for 6h and 24h, 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 (10μM) and JAK/STAT inhibitor WP1066 (5μM) but were largely aggravated by ACE2 inhibitor DX600 (0.5μM). More importantly, treatment with human recombinant ACE2 (hrACE2; 1mg/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 (50nM) 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.