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Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy: role of Akt-FoxO-signaling network

Gene Therapy volume 17, pages 478–485 (2010)Cite this article

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Abstract

Recent studies suggest that glutaredoxin-1 (Glrx-1) may serve as therapeutic target for diabetic hearts. As the level of reactive oxygen species (ROS) is increased in the pathologic hearts including ischemia/reperfusion (I/R) and diabetes, we assumed that upregulation of Glrx-1 could reduce the cardiac risk factors associated with I/R and/or diabetes. Diabetes was induced in mice by i.p. injection of streptozotocin (150 mg kg−1). Eight days after when the blood glucose was elevated to 400 mg per 100 ml, the animals were randomly assigned to one of the following three groups, which received either empty vector, or LacZ or Glrx-1 adenoviral construct. Four days later, isolated working hearts were subjected to 30 min ischemia followed by 2 h reperfusion. Glrx-1 gene therapy significantly enhanced the Glrx-1 level, which prevented I/R-mediated reduction of ventricular recovery, increased myocardial infarct size and cardiomyocyte apoptosis in diabetic myocardium. In concert, Glrx-1 prevented diabetes and ischemia–reperfusion induced reduction of cardioprotective proteins including Akt, FoxO-1, and hemeoxygenase-1, and abolished the death signal triggered by Jnk, p38 mitogen-activated protein kinase, and c-Src. Glrx-1 gene therapy seems to prevent cardiac complications in diabetic heart due to the I/R by switching the death signal into survival signal by activating Akt-FoxO-signaling network.

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Acknowledgements

This study was supported by National Heart, Lung, and Blood Institute Grants NIH HL-22559, HL-33889, HL-34360, OTKA 72315 and TAMOP-4.2.2-08/1-2008-0007.

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Authors and Affiliations

  1. Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, USA

    I Lekli, S Mukherjee, D Ray, N Gurusamy, Y H Kim, R M Engelman & D K Das

  2. Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary

    I Lekli & A Tosaki

  3. Department of Anaesthesiology and Pain Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

    Y H Kim

  4. Wayne State University, Detroit, MI, USA

    Y-S Ho

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  1. I Lekli
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Correspondence to D K Das.

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Lekli, I., Mukherjee, S., Ray, D. et al. Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy: role of Akt-FoxO-signaling network. Gene Ther 17, 478–485 (2010). https://doi.org/10.1038/gt.2010.9

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