Role of tissue transglutaminase in age-associated ventricular stiffness

Young Jun Oh, Vanessa C. Pau, Jochen Steppan, Gautam Sikka, Valeriani R. Bead, Daniel Nyhan, Benjamin D. Levine, Dan E Berkowitz, Lakshmi Santhanam

Research output: Contribution to journalArticle

Abstract

Aging is associated with increased cardiomyocyte loss, left-ventricular hypertrophy, and the accumulation of extracellular matrix, which results in declining cardiac function. The role of the matrix crosslinking enzyme, tissue transglutaminase (TG2), in age-related myocardial stiffness, and contractile function remains incompletely understood. In this study, we examined the role of TG2 in cardiac function, and determined whether TG2 inhibition can prevent age-associated changes in cardiac function. Male Fisher rats (18-month-old) were administered the transglutaminase inhibitor cystamine (study group) or saline (age-matched controls) for 12 weeks via osmotic mini-pumps. Cardiac function was determined by echocardiography and invasive pressure–volume loops. Rat hearts were dissected out, and TG2 expression, activity, and S-nitrosation were determined. Young (6-month-old) males were used as controls. TG2 activity significantly increased in the saline-treated but not in the cystamine-treated aging rat hearts. TG2 expression also increased with age and was unaltered by cystamine treatment. Aged rats showed increased left ventricular (LV) end-systolic dimension and a decrease in fractional shortening compared with young, which was not affected by cystamine. However, cystamine treatment preserved the preload-independent index of LV filling pressure and restored end-diastolic pressure, end-diastolic pressure–volume relationships, and arterial elastance toward young. An increase in TG2 activity contributes to age-associated increase in diastolic stiffness, thereby contributing to age-associated diastolic dysfunction. TG2 may thus represent a novel target for age-associated diastolic heart failure.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalAmino Acids
DOIs
StateAccepted/In press - Jul 20 2016

Keywords

  • Cardiac aging
  • Hypertrophy
  • Tissue transglutaminase

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Oh, Y. J., Pau, V. C., Steppan, J., Sikka, G., Bead, V. R., Nyhan, D., Levine, B. D., Berkowitz, D. E., & Santhanam, L. (Accepted/In press). Role of tissue transglutaminase in age-associated ventricular stiffness. Amino Acids, 1-10. https://doi.org/10.1007/s00726-016-2295-z