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Insulin augments serotonin-induced contraction via activation of the IR/PI3K/PDK1 pathway in the rat carotid artery

  • Molecular and cellular mechanisms of disease
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Abstract

Hyperinsulinemia associated with type 2 diabetes may contribute to the development of vascular diseases. Although we recently reported that enhanced contractile responses to serotonin (5-hydroxytryptamine, 5-HT) are observed in the arteries of type 2 diabetes models, the causative factors and detailed signaling pathways involved remain unclear. The purpose of this study was to investigate whether high insulin would be an amplifier of 5-HT-induced contraction in rat carotid arteries and whether the contraction involves phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1) signaling, an insulin-mediated signaling pathway. In rat carotid arteries organ-cultured with insulin (for 24 h), (1) the contractile responses to 5-HT were significantly greater (vs. vehicle), (2) the insulin-induced enhancement of 5-HT-induced contractions was largely suppressed by inhibitors of the insulin receptor (IR) (GSK1838705A), PI3K (LY294002), and PDK1 (GSK2334470), and (3) the levels of phosphorylated forms of both PDK1 and myosin phosphatase target subunit 1 (MYPT1) were greater upon 5-HT stimulation. In addition, in rat carotid arteries organ-cultured with an activator of PDK1 (PS48), the 5-HT-induced contraction was greater, and this was suppressed by PDK1 inhibition but not PI3K inhibition. In addition, MYPT1 and PDK1 phosphorylation upon 5-HT stimulation was enhanced (vs. vehicle). These results suggest that high insulin levels amplify 5-HT-induced contraction. Moreover, the present results indicated the direct linkage between IR/PI3K/PDK1 activation and 5-HT-induced contraction in rat carotid arteries for the first time.

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Acknowledgments

We thank T. Adachi, K. Matsubara, Y. Noishiki, Y. Kimoto, H. Higa, M. Nagata, M. Ando, and M. Iguchi for technical assistance. This study was supported in part by JSPS KAKENHI Grant Numbers 26460107, 15K21419, and 15K07975.

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    1. Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

      Shun Watanabe, Takayuki Matsumoto, Mirai Oda, Kosuke Yamada, Junya Takagi, Kumiko Taguchi & Tsuneo Kobayashi

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    Shun Watanabe and Takayuki Matsumoto contributed equally to this work.

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    Watanabe, S., Matsumoto, T., Oda, M. et al. Insulin augments serotonin-induced contraction via activation of the IR/PI3K/PDK1 pathway in the rat carotid artery. Pflugers Arch - Eur J Physiol 468, 667–677 (2016). https://doi.org/10.1007/s00424-015-1759-4

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