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Articles by H. Miyazaki
Total Records ( 2 ) for H. Miyazaki
  H Shimizu , Y Hirose , F Nishijima , Y Tsubakihara and H. Miyazaki

Patients with chronic renal failure are at greater risk of developing atherosclerosis than healthy individuals, and recent data suggest that the putative uremic toxin indoxyl sulfate (IS) promotes the pathogenesis of atherosclerosis. The present study examined the effects of IS on vascular smooth muscle cells (VSMCs) with respect to reactive oxygen species (ROS), platelet-derived growth factor (PDGF) receptors, and mitogen-activated protein kinases (MAPKs). IS induced the migration and proliferation of VSMCs and synergistically enhanced their PDGF-induced migration as well as proliferation. The effects of PDGF were promoted after a 24-h incubation with IS despite the absence of IS during PDGF stimulation. Intracellular ROS levels were increased in the presence of IS, and PDGF-dependent ROS production was augmented by a prior 24-h incubation with IS even in the absence of IS during PDGF stimulation. These data suggest that IS increases the sensitivity of VSMCs to PDGF. IS also phosphorylated PDGF-β-receptors and upregulated PDGF-β receptor but not -receptor protein expression in the absence of exogenous PDGF. The NADPH oxidase inhibitor diphenylene iodonium blocked IS-dependent increase in receptor expression. Administration of IS to nephrectomized rats also elevated receptor protein expression in arterial VSMCs. Inhibitors of NADPH oxidase, PDGF-β receptors, extracellular-regulated protein kinase (ERK), and p38 MAPK all inhibited IS-induced VSMCs migration and proliferation. Taken together, these findings indicate that IS induces the migration as well as proliferation of VSMCs through PDGF-β receptors and that ROS generation is critically involved in this process, which promotes the development of atherosclerosis.

  H Shimizu , Y Nakagawa , C Murakami , N Aoki , S Kim Mitsuyama and H. Miyazaki

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 M (PTPM) promotes VEC survival and migration. The present study investigates the biological functions of PTPM in VSMCs and determines whether PTPM is implicated in diabetes-accelerated atherosclerosis. We overexpressed wild-type and inactive PTPM and an small interfering RNA (siRNA) of PTPM by using an adenovirus vector to investigate the effects of PTPM upon platelet-derived growth factor (PDGF)- and high glucose (HG)-induced responses of rat VSMCs in vitro. We found that PTPM 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 PTPM. The PDGFR inhibitor AG1296 also blocked HG-induced Nox1 expression and H2O2 production. Moreover, HG suppressed PTPM expression itself, which was blocked by the antioxidant N-acetyl-l-cysteine. The effects of PTPM siRNA were the opposite of those of wild-type PTPM. Therefore, PTPM negatively regulates PDGFRβ-mediated signaling pathways that are crucial for the pathogenesis of atherosclerosis, and PTPM may be involved in diabetes-accelerated atherosclerosis.

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