Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness

Lakshmi Santhanam, Eric C. Tuday, Alanah K. Webb, Phillip Dowzicky, Jae Hyung Kim, Young Jun Oh, Gautam Sikka, Maggie Kuo, Marc K. Halushka, Anne M. MacGregor, Jessilyn Dunn, Sarah Gutbrod, David Yin, Artin Shoukas, Daniel Nyhan, Nicholas A. Flavahan, Alexey M. Belkin, Dan E. Berkowitz

Research output: Contribution to journalArticle

Abstract

Rationale: Although an age-related decrease in NO bioavailability contributes to vascular stiffness, the underlying molecular mechanisms remain incompletely understood. We hypothesize that NO constrains the activity of the matrix crosslinking enzyme tissue transglutaminase (TG2) via S-nitrosylation in young vessels, a process that is reversed in aging. Objective: We sought to determine whether endothelium-dependent NO regulates TG2 activity by S-nitrosylation and whether this contributes to age-related vascular stiffness. Methods and Results: We first demonstrate that NO suppresses activity and increases S-nitrosylation of TG2 in cellular models. Next, we show that nitric oxide synthase (NOS) inhibition leads to increased surface and extracellular matrix-associated TG2. We then demonstrate that endothelium-derived bioactive NO primarily mediates its effects through TG2, using TG2-/- mice chronically treated with the NOS inhibitor l-NG-nitroarginine methyl ester (L-NAME). We confirm that TG2 activity is modulated by endothelium-derived bioactive NO in young rat aorta. In aging rat aorta, although TG2 expression remains unaltered, its activity increases and S-nitrosylation decreases. Furthermore, TG2 inhibition decreases vascular stiffness in aging rats. Finally, TG2 activity and matrix crosslinks are augmented with age in human aorta, whereas abundance remains unchanged. Conclusions: Decreased S-nitrosylation of TG2 and increased TG activity lead to enhanced matrix crosslinking and contribute to vascular stiffening in aging. TG2 appears to be the member of the transglutaminase family primarily contributing to this phenotype. Inhibition of TG2 could thus represent a therapeutic target for age-associated vascular stiffness and isolated systolic hypertension.

Original languageEnglish (US)
Pages (from-to)117-125
Number of pages9
JournalCirculation research
Volume107
Issue number1
DOIs
StatePublished - Jul 9 2010

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Keywords

  • Aging
  • S-nitrosation
  • S-nitrosylation
  • Tissue transglutaminase
  • Vascular stiffness

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Santhanam, L., Tuday, E. C., Webb, A. K., Dowzicky, P., Kim, J. H., Oh, Y. J., Sikka, G., Kuo, M., Halushka, M. K., MacGregor, A. M., Dunn, J., Gutbrod, S., Yin, D., Shoukas, A., Nyhan, D., Flavahan, N. A., Belkin, A. M., & Berkowitz, D. E. (2010). Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness. Circulation research, 107(1), 117-125. https://doi.org/10.1161/CIRCRESAHA.109.215228