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Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats

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Abstract

Hyperglycemia-induced reactive oxygen species (ROS) production plays a major role in the pathogenesis of diabetic vascular dysfunction. However, the underlying mechanisms remain unclear. Toll-like receptor 4 (TLR4), a key component of innate immunity, is known to be activated during diabetes. Therefore, we hypothesize that hyperglycemia activates TLR4 signaling in vascular smooth muscle cells (VSMCs) that triggers ROS production and causes vascular dysfunction. Rat mesenteric VSMCs exposed to high glucose (25 mmol/l) increased TLR4 expression and activated TLR4 signaling via upregulation of myeloid differentiation factor 88 (MyD88). TLR4 inhibitor CLI-095 significantly attenuated elevated levels of ROS and nuclear factor-kappa B (NF-κB) activity in VSMCs exposed to high glucose. Mesenteric arteries from streptozotocin-induced diabetic rats treated with CLI-095 (2 mg/kg/day) intraperitoneally for 2 weeks exhibited reduced ROS generation and attenuated noradrenaline-induced contraction. These results suggest that hyperglycemia-induced ROS generation and NF-κB activation in VSMCs are at least, in part, mediated by TLR4 signaling. Therefore, strategies to block TLR4 signaling pathways pose a promising avenue to alleviate diabetic-induced vascular complications.

Key messages

  • High glucose-induced TLR4 activation in vascular smooth muscle cells.

  • Inhibition of TLR4 attenuated high glucose-induced ROS production and NF-κB activity in VSMC.

  • Suppression of TLR4 signaling attenuated mesenteric contraction in diabetic rat.

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Funding

This work was supported by research grants from American Heart Association to M.A. Carrillo-Sepulveda (13POST14690026) and D. Pandey (13POST16810011).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology, Georgia Regents University, Augusta, GA, USA

    Maria Alicia Carrillo-Sepulveda

  2. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

    Kathryn Spitler

  3. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Deepesh Pandey & Dan E. Berkowitz

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

    Takayuki Matsumoto

  5. Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Northern Blvd., Old Westbury, NY, 11568, USA

    Maria Alicia Carrillo-Sepulveda

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  1. Maria Alicia Carrillo-Sepulveda
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Correspondence to Maria Alicia Carrillo-Sepulveda.

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Carrillo-Sepulveda, M.A., Spitler, K., Pandey, D. et al. Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats. J Mol Med 93, 1341–1354 (2015). https://doi.org/10.1007/s00109-015-1318-7

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