ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells |
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Authors: | Izawa Yuki Yoshizumi Masanori Fujita Yoshiko Ali Nermin Kanematsu Yasuhisa Ishizawa Keisuke Tsuchiya Koichiro Obata Toshiyuki Ebina Yousuke Tomita Shuhei Tamaki Toshiaki |
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Affiliation: | a Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto 770-8503, Japan;b Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima Graduate School, Japan;c Division of Experimental Immunology, Institute for Genome Research, The University of Tokushima Graduate School, Japan |
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Abstract: | Clinical evidence suggests a relationship between hypertension and insulin resistance, and cross-talk between angiotensin II (Ang II) and insulin signaling pathways may take place. We now report the effect of Ang II on insulin-induced glucose uptake and its intracellular mechanisms in vascular smooth muscle cells (VSMC). We examined the translocation of glucose transporter-4 (GLUT-4) and glucose uptake in rat aortic smooth muscle cells (RASMC). Mitogen-activated protein (MAP) kinases and Akt activities, and phosphorylation of insulin receptor substrate-1 (IRS-1) at the serine and tyrosine residues were measured by immunoprecipitation and immunoblotting. As a result, Ang II inhibited insulin-induced GLUT-4 translocation from cytoplasm to the plasma membrane in RASMC. Ang II induced extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation and IRS-1 phosphorylation at Ser307 and Ser616. Ang II-induced Ser307 and Ser616 phophorylation of IRS-1 was inhibited by a MEK inhibitor, PD98059, and a JNK inhibitor, SP600125. Ang II inhibition of insulin-stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125. Ang II inhibited insulin-induced glucose uptake, which was also reversed by PD98059 but not by SP600125. It is shown that Ang II-induced ERK1/2 activation inhibits insulin-dependent glucose uptake through serine phophorylation of IRS-1 in RASMC. |
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Keywords: | Insulin resistance Angiotensin II Vascular smooth muscle cell Glucose uptake MAP kinase IRS-1 |
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