Skip to main content

Advertisement

SpringerLink
Log in

Role of tissue transglutaminase in age-associated ventricular stiffness

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Arza P, Netti V, Perosi F, Cernadas G, Ochoa F, Magnani N, Evelson P, Zotta E, Fellet A, Balaszczuk AM (2015) Involvement of nitric oxide and caveolins in the age-associated functional and structural changes in a heart under osmotic stress. Biomed Pharmacother 69:380–387. doi:10.1016/j.biopha.2014.12.026

    Article  CAS  PubMed  Google Scholar 

  • Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ (2000) An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 97(6):2809–2813. doi:10.1073/pnas.040558497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Avery NC, Bailey AJ (2005) Enzymic and non-enzymic cross-linking mechanisms in relation to turnover of collagen: relevance to aging and exercise. Scand J Med Sci Sports 15(4):231–240. doi:10.1111/j.1600-0838.2005.00464.x

    Article  CAS  PubMed  Google Scholar 

  • Bakker EN, Buus CL, Spaan JA, Perree J, Ganga A, Rolf TM, Sorop O, Bramsen LH, Mulvany MJ, Vanbavel E (2005) Small artery remodeling depends on tissue-type transglutaminase. Circ Res 96(1):119–126. doi:10.1161/01.RES.0000151333.56089.66

    Article  CAS  PubMed  Google Scholar 

  • Baumgartner W, Golenhofen N, Weth A, Hiiragi T, Saint R, Griffin M, Drenckhahn D (2004) Role of transglutaminase 1 in stabilisation of intercellular junctions of the vascular endothelium. Histochem Cell Biol 122(1):17–25

    Article  CAS  PubMed  Google Scholar 

  • Beazley KE, Banyard D, Lima F, Deasey SC, Nurminsky DI, Konoplyannikov M, Nurminskaya MV (2013) Transglutaminase inhibitors attenuate vascular calcification in a preclinical model. Arterioscler Thromb Vasc Biol 33(1):43–51. doi:10.1161/ATVBAHA.112.300260

    Article  CAS  PubMed  Google Scholar 

  • Beckouche N, Bignon M, Lelarge V, Mathivet T, Pichol-Thievend C, Berndt S, Hardouin J, Garand M, Ardidie-Robouant C, Barret A, Melino G, Lortat-Jacob H, Muller L, Monnot C, Germain S (2015) The interaction of heparan sulfate proteoglycans with endothelial transglutaminase-2 limits VEGF165-induced angiogenesis. Sci Signal 8(385):ra70. doi:10.1126/scisignal.aaa0963

    Article  PubMed  Google Scholar 

  • Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ, Rodeheffer RJ (2013) Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail 6(5):944–952. doi:10.1161/CIRCHEARTFAILURE.113.000383

    Article  PubMed  Google Scholar 

  • Connelly KA, Prior DL, Kelly DJ, Feneley MP, Krum H, Gilbert RE (2006) Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures. Am J Physiol Heart Circ Physiol 290(4):H1699–H1705

    Article  CAS  PubMed  Google Scholar 

  • Eng J, McClelland RL, Gomes AS, Hundley WG, Cheng S, Wu CO, Carr JJ, Shea S, Bluemke DA, Lima JA (2016) Adverse left ventricular remodeling and age assessed with cardiac MR imaging: the multi-ethnic study of atherosclerosis. Radiology 278(3):714–722. doi:10.1148/radiol.2015150982

    Article  PubMed  Google Scholar 

  • Fesus L, Thomazy V (1988) Searching for the function of tissue transglutaminase: its possible involvement in the biochemical pathway of programmed cell death. Adv Exp Med Biol 231:119–134

    CAS  PubMed  Google Scholar 

  • Folk JE, Cole PW (1965) Structural Requirements of Specific Substrates for Guinea Pig Liver Transglutaminase. J Biol Chem 240:2951–2960

    CAS  PubMed  Google Scholar 

  • Folkow B, Svanborg A (1993) Physiology of cardiovascular aging. Physiol Rev 73(4):725–764

    CAS  PubMed  Google Scholar 

  • Hees PS, Fleg JL, Lakatta EG, Shapiro EP (2002) Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. Am J Cardiol 90(11):1231–1236

    Article  PubMed  Google Scholar 

  • Horn MA, Trafford AW (2016) Aging and the cardiac collagen matrix: novel mediators of fibrotic remodelling. J Mol Cell Cardiol 93:175–185. doi:10.1016/j.yjmcc.2015.11.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jandu SK, Webb AK, Pak A, Sevinc B, Nyhan D, Belkin AM, Flavahan NA, Berkowitz DE, Santhanam L (2013) Nitric oxide regulates tissue transglutaminase localization and function in the vasculature. Amino Acids 44(1):261–269. doi:10.1007/s00726-011-1090-0

    Article  CAS  PubMed  Google Scholar 

  • Jung SM, Jandu S, Steppan J, Belkin A, An SS, Pak A, Choi EY, Nyhan D, Butlin M, Viegas K, Avolio A, Berkowitz DE, Santhanam L (2013) Increased tissue transglutaminase activity contributes to central vascular stiffness in eNOS knockout mice. Am J Physiol Heart Circ Physiol 305(6):H803–H810. doi:10.1152/ajpheart.00103.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jyothirmayi GN, Soni BJ, Masurekar M, Lyons M, Regan TJ (1998) Effects of metformin on collagen glycation and diastolic dysfunction in diabetic myocardium. J Cardiovasc Pharmacol Ther 3(4):319–326. doi:10.1053/jcpt.1998.0319

    Article  CAS  PubMed  Google Scholar 

  • Kass DA (2005) Ventricular arterial stiffening: integrating the pathophysiology. Hypertension 46(1):185–193. doi:10.1161/01.HYP.0000168053.34306.d4

    Article  CAS  PubMed  Google Scholar 

  • Katz DH, Beussink L, Sauer AJ, Freed BH, Burke MA, Shah SJ (2013) Prevalence, clinical characteristics, and outcomes associated with eccentric versus concentric left ventricular hypertrophy in heart failure with preserved ejection fraction. Am J Cardiol 112(8):1158–1164. doi:10.1016/j.amjcard.2013.05.061

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim JH, Choy HE, Nam KH, Park SC (2001) Transglutaminase-mediated crosslinking of specific core histone subunits and cellular senescence. Ann N Y Acad Sci 928:65–70

    Article  CAS  PubMed  Google Scholar 

  • Lai TS, Hausladen A, Slaughter TF, Eu JP, Stamler JS, Greenberg CS (2001) Calcium regulates S-nitrosylation, denitrosylation, and activity of tissue transglutaminase. Biochemistry 40(16):4904–4910

    Article  CAS  PubMed  Google Scholar 

  • Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4(2):140–156. doi:10.1038/nrm1014

    Article  CAS  PubMed  Google Scholar 

  • Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD (2016) Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 29(4):277–314. doi:10.1016/j.echo.2016.01.011

    Article  PubMed  Google Scholar 

  • Najjar SS, Scuteri A, Lakatta EG (2005) Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 46(3):454–462. doi:10.1161/01.HYP.0000177474.06749.98

    Article  CAS  PubMed  Google Scholar 

  • Nanda N, Iismaa SE, Owens WA, Husain A, Mackay F, Graham RM (2001) Targeted inactivation of Gh/tissue transglutaminase II. J Biol Chem 276(23):20673–20678

    Article  CAS  PubMed  Google Scholar 

  • Ouzounian M, Lee DS, Liu PP (2008) Diastolic heart failure: mechanisms and controversies. Nat Clin Pract Cardiovasc Med 5(7):375–386. doi:10.1038/ncpcardio1245

    Article  PubMed  Google Scholar 

  • Pacher P, Mabley JG, Liaudet L, Evgenov OV, Marton A, Hasko G, Kollai M, Szabo C (2004) Left ventricular pressure-volume relationship in a rat model of advanced aging-associated heart failure. Am J Physiol Heart Circ Physiol 287(5):H2132–H2137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park SC, Yeo EJ, Han JA, Hwang YC, Choi JY, Park JS, Park YH, Kim KO, Kim IG, Seong SC, Kwak SJ (1999) Aging process is accompanied by increase of transglutaminase C. J Gerontol A Biol Sci Med Sci 54(2):B78–B83

    Article  CAS  PubMed  Google Scholar 

  • Petrak J, Pospisilova J, Sedinova M, Jedelsky P, Lorkova L, Vit O, Kolar M, Strnad H, Benes J, Sedmera D, Cervenka L, Melenovsky V (2011) Proteomic and transcriptomic analysis of heart failure due to volume overload in a rat aorto-caval fistula model provides support for new potential therapeutic targets—monoamine oxidase A and transglutaminase 2. Proteome Sci 9(1):69. doi:10.1186/1477-5956-9-69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sane DC, Kontos JL, Greenberg CS (2007) Roles of transglutaminases in cardiac and vascular diseases. Front Biosci 12:2530–2545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santhanam L, Tuday EC, Webb AK, Dowzicky P, Kim JH, Oh YJ, Sikka G, Kuo M, Halushka MK, Macgregor AM, Dunn J, Gutbrod S, Yin D, Shoukas A, Nyhan D, Flavahan NA, Belkin AM, Berkowitz DE (2010) Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness. Circ Res 107(1):117–125. doi:10.1161/CIRCRESAHA.109.215228

    Article  CAS  PubMed  Google Scholar 

  • Santhanam L, Berkowitz DE, Belkin AM (2011) Nitric oxide regulates non-classical secretion of tissue transglutaminase. Commun Integr Biol 4(5):584–586. doi:10.4161/cib.4.5.16512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schertel ER (1998) Assessment of left-ventricular function. Thorac Cardiovasc Surg 46(Suppl 2):248–254

    Article  PubMed  Google Scholar 

  • Shcwartz J (2007) Braunwald’s heart disease: a textbook of cardiovascular medicine. Saunders, Philadelphia

    Google Scholar 

  • Sheydina A, Riordon DR, Boheler KR (2011) Molecular mechanisms of cardiomyocyte aging. Clin Sci (Lond) 121(8):315–329. doi:10.1042/CS20110115

    Article  CAS  Google Scholar 

  • Siegel M, Khosla C (2007) Transglutaminase 2 inhibitors and their therapeutic role in disease states. Pharmacol Ther 115(2):232–245. doi:10.1016/j.pharmthera.2007.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sindler AL, Fleenor BS, Calvert JW, Marshall KD, Zigler ML, Lefer DJ, Seals DR (2011) Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Aging Cell 10(3):429–437. doi:10.1111/j.1474-9726.2011.00679.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Small K, Feng JF, Lorenz J, Donnelly ET, Yu A, Im MJ, Dorn GW 2nd, Liggett SB (1999) Cardiac specific overexpression of transglutaminase II (G(h)) results in a unique hypertrophy phenotype independent of phospholipase C activation. J Biol Chem 274(30):21291–21296

    Article  CAS  PubMed  Google Scholar 

  • Steppan J, Sikka G, Jandu S, Barodka V, Halushka MK, Flavahan NA, Belkin AM, Nyhan D, Butlin M, Avolio A, Berkowitz DE, Santhanam L (2014) Exercise, vascular stiffness, and tissue transglutaminase. J Am Heart Assoc 3(2):e000599. doi:10.1161/JAHA.113.000599

    Article  PubMed  PubMed Central  Google Scholar 

  • Szondy Z, Mastroberardino PG, Varadi J, Farrace MG, Nagy N, Bak I, Viti I, Wieckowski MR, Melino G, Rizzuto R, Tosaki A, Fesus L, Piacentini M (2006) Tissue transglutaminase (TG2) protects cardiomyocytes against ischemia/reperfusion injury by regulating ATP synthesis. Cell Death Differ 13(10):1827–1829

    Article  CAS  PubMed  Google Scholar 

  • van den Akker J, VanBavel E, van Geel R, Matlung HL, Guvenc Tuna B, Janssen GM, van Veelen PA, Boelens WC, De Mey JG, Bakker EN (2011) The redox state of transglutaminase 2 controls arterial remodeling. PLoS One 6(8):e23067. doi:10.1371/journal.pone.0023067

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang M, Shah AM (2015) Age-associated pro-inflammatory remodeling and functional phenotype in the heart and large arteries. J Mol Cell Cardiol 83:101–111. doi:10.1016/j.yjmcc.2015.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao J, Randive R, Stewart JA (2014) Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart. World J Diabetes 5(6):860–867. doi:10.4239/wjd.v5.i6.860

    Article  PubMed  PubMed Central  Google Scholar 

  • Zito C, Mohammed M, Todaro MC, Khandheria BK, Cusma-Piccione M, Oreto G, Pugliatti P, Abusalima M, Antonini-Canterin F, Vriz O, Carerj S (2014) Interplay between arterial stiffness and diastolic function: a marker of ventricular-vascular coupling. J Cardiovasc Med (Hagerstown) 15(11):788–796. doi:10.2459/JCM.0000000000000093

    Article  Google Scholar 

Download references

Acknowledgments

This work was funded by an American Heart Association Beginning Grant-in-Aid 09BGIA2220181 (to LS) and National Heart, Lung, and Blood Institute grants R01HL105296 (to DEB) and R01AG017479 (to BDL).

Author information

Author notes

    Authors and Affiliations

    1. Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD, 21205, USA

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

    2. Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea

      Young Jun Oh

    3. University of Texas Southwestern Medical Center, Dallas, USA

      Benjamin D. Levine

    Authors
    1. Young Jun Oh
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Vanessa C. Pau
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jochen Steppan
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Gautam Sikka
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Valeriani R. Bead
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Daniel Nyhan
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Benjamin D. Levine
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Dan E. Berkowitz
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Lakshmi Santhanam
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Lakshmi Santhanam.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Research involving human participants and/or animals

    This article does not contain any studies with human subjects by any of the authors. For the rodent studies, all applicable international, national, and institutional guidelines for the care and use of laboratory animals were followed. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Johns Hopkins University, School of Medicine.

    Additional information

    Handling Editors: S. Beninati, M. Piacentini, C.M. Bergamini.

    Y. J. Oh and V. C. Pau contributed equally to this work.

    D. E. Berkowitz and L. Santhanam contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Oh, Y.J., Pau, V.C., Steppan, J. et al. Role of tissue transglutaminase in age-associated ventricular stiffness. Amino Acids 49, 695–704 (2017). https://doi.org/10.1007/s00726-016-2295-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00726-016-2295-z

    Keywords

    Search

    Navigation