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Nitric oxide regulates tissue transglutaminase localization and function in the vasculature

Amino Acids volume 44, pages 261–269 (2013)Cite this article

Abstract

The multifunctional enzyme tissue transglutaminase (TG2) contributes to the development and progression of several cardiovascular diseases. Extracellular rather than intracellular TG2 is enzymatically active, however, the mechanism by which it is exported out of the cell remains unknown. Nitric oxide (NO) is shown to constrain TG2 externalization in endothelial and fibroblast cells. Here, we examined the role of both exogenous and endogenous (endothelial cell-derived) NO in regulating TG2 localization in vascular cells and tissue. NO synthase inhibition in endothelial cells (ECs) using N-nitro l-arginine methyl ester (l-NAME) led to a time-dependent decrease in S-nitrosation and increase in externalization of TG2. Laminar shear stress led to decreased extracellular TG2 in ECs. S-nitrosoglutathione treatment led to decreased activity and externalization of TG2 in human aortic smooth muscle and fibroblast (IMR90) cells. Co-culture of these cells with ECs resulted in increased S-nitrosation and decreased externalization and activity of TG2, which was reversed by l-NAME. Aged Fischer 344 rats had higher tissue scaffold-associated TG2 compared to young. NO regulates intracellular versus extracellular TG2 localization in vascular cells and tissue, likely via S-nitrosation. This in part, explains increased TG2 externalization and activity in aging aorta.

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Acknowledgments

This work was supported by an American Heart Association Grant 09BGIA2220181 to LS and a National Institutes of Health Grant 1R01-HL105296-01 to DEB.

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Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA

    Simran K. Jandu, Alanah K. Webb, Daniel Nyhan, Nicholas A. Flavahan, Dan E. Berkowitz & Lakshmi Santhanam

  2. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA

    Alina Pak, Baris Sevinc & Dan E. Berkowitz

  3. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 800 W Baltimore St, Room 213, Baltimore, MD, 21201, USA

    Alexey M. Belkin

Authors
  1. Simran K. Jandu
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  2. Alanah K. Webb
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  3. Alina Pak
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  4. Baris Sevinc
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  5. Daniel Nyhan
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  6. Alexey M. Belkin
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  7. Nicholas A. Flavahan
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  8. Dan E. Berkowitz
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  9. Lakshmi Santhanam
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Corresponding authors

Correspondence to Dan E. Berkowitz or Lakshmi Santhanam.

Additional information

S. K. Jandu and A. K. Webb contributed equally to this work.

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Jandu, S.K., Webb, A.K., Pak, A. et al. Nitric oxide regulates tissue transglutaminase localization and function in the vasculature. Amino Acids 44, 261–269 (2013). https://doi.org/10.1007/s00726-011-1090-0

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  • DOI: https://doi.org/10.1007/s00726-011-1090-0

Keywords

  • Aging
  • Tissue transglutaminase
  • Nitric oxide
  • S-nitrosation