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

Putative protective mechanisms of angiotensin-converting enzyme 2 (ACE2) against Ang II-mediated oxidative stress and VSMC proliferation. In this work, a marked elevation in suppressors of cytokine signaling 3 (SOCS3) expression induced by angiotensin II (Ang II) was observed in cultured human umbilical artery smooth muscle cells (HUASMCs), accompanied by significant increases in phosphorylation levels of Janus kinase 2 (JAK2), signal transducer and activators of transcription 3 (STAT3) and extracellular regulated protein kinases 1/2 (ERK1/2), leading to augmented superoxide production and cell proliferation. These changes were strikingly reversed by administration of human recombinant ACE2, ERK1/2 inhibitor PD98059 and JAK/STAT inhibitor WP1066 but were largely aggravated by pharmacological inhibition of ACE2 with DX600. Taken together, treatment with recombinant ACE2 strikingly prevented Ang II/AT1 receptor-mediated activation of JAK2/STAT3/SOCS3 and profilin-1/ERK1/2 signaling pathways, subsequently contributing to attenuation of superoxide generation and VSMC proliferation.