Protein tyrosine phosphatase PTPεM negatively regulates PDGF β-receptor signaling induced by high glucose and PDGF in vascular smooth muscle cells

Abstract

Vascular smooth muscle cell (VSMC) proliferation and migration and vascular endothelial cell (VEC) dysfunction are closely associated with the development of atherosclerosis. We previously demonstrated that protein tyrosine phosphatase ε M (PTPεM) promotes VEC survival and migration. The present study investigates the biological functions of PTPεM in VSMCs and determines whether PTPεM is implicated in diabetes-accelerated atherosclerosis. We overexpressed wild-type and inactive PTPεM and an small interfering RNA (siRNA) of PTPεM by using an adenovirus vector to investigate the effects of PTPεM upon platelet-derived growth factor (PDGF)- and high glucose (HG)-induced responses of rat VSMCs in vitro. We found that PTPεM decreased PDGF-induced DNA synthesis and migration by reducing the phosphorylation level of the PDGF β-receptor (PDGFRβ) with subsequently suppressed H2O2 generation. The HG content in the medium generated H2O2, upregulated PDGFRβ expression and its tyrosine-phosphorylation, and elevated NADPH oxidase 1 (Nox1) expression even without exogenous PDGF, all of which were downregulated by PTPεM. The PDGFR inhibitor AG1296 also blocked HG-induced Nox1 expression and H2O2 production. Moreover, HG suppressed PTPεM expression itself, which was blocked by the antioxidant N-acetyl-l-cysteine. The effects of PTPεM siRNA were the opposite of those of wild-type PTPεM. Therefore, PTPεM negatively regulates PDGFRβ-mediated signaling pathways that are crucial for the pathogenesis of atherosclerosis, and PTPεM may be involved in diabetes-accelerated atherosclerosis.