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Research ArticleCardiovascular

Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

Shiliu Tian, Xinfa Ge, Ke Wu, Huabing Yang and Yu Liu
Journal of Pharmacology and Experimental Therapeutics July 2014, 350 (1) 5-13; DOI: https://doi.org/10.1124/jpet.114.212928
Shiliu Tian
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.)
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Xinfa Ge
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.)
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Ke Wu
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.)
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Huabing Yang
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.)
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Yu Liu
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.)
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Abstract

This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKβ (Ca2+/calmodulin-dependent protein kinase kinase-β) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2–related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKβ/AMPK pathway–dependent manner, leading to increased expression of the Nrf-2–regulated antioxidant enzyme, HO-1. The inhibition of CaMKKβ or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-β, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function.

Footnotes

    • Received January 14, 2014.
    • Accepted April 16, 2014.
  • Y.L. is the guarantor of this work, had full access to all the data, and takes full responsibility for the integrity of data and the accuracy of data analysis. S.T. and K.W. contributed equally to this work.

  • dx.doi.org/10.1124/jpet.114.212928.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 1
1 Jul 2014
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Research ArticleCardiovascular

Ramipril Activates AMPK

Shiliu Tian, Xinfa Ge, Ke Wu, Huabing Yang and Yu Liu
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 5-13; DOI: https://doi.org/10.1124/jpet.114.212928

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Research ArticleCardiovascular

Ramipril Activates AMPK

Shiliu Tian, Xinfa Ge, Ke Wu, Huabing Yang and Yu Liu
Journal of Pharmacology and Experimental Therapeutics July 1, 2014, 350 (1) 5-13; DOI: https://doi.org/10.1124/jpet.114.212928
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