Skip to main content

Advertisement

SpringerLink
Log in

Upregulation of arginase-II contributes to decreased age-related myocardial contractile reserve

  • Original Article
  • Published:
European Journal of Applied Physiology Aims and scope Submit manuscript

An Erratum to this article was published on 05 October 2012

Abstract

Arginase-II (Arg-II) reciprocally regulates nitric oxide synthase (NOS) and offsets basal myocardial contractility. Furthermore, decreased or absent myocardial NOS activity is associated with a depression in myocardial contractile reserve. We therefore hypothesized that upregulation of Arg-II might in part be responsible for depressed myocardial contractility associated with age. We studied arginase activity/expression, NOS expression, NO production in the presence and absence of the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) in old (22 months) and young (3 months) rat hearts and myocytes. The spatial confinement of Arg-II and NOS was determined with immuno-electron-miocrographic (IEM) and immuno-histochemical studies. We tested the effect of BEC on the force frequency response (FFR) in myocytes, as well as NOS abundance and activity. Arginase activity and Arg-II expression was increased in old hearts (2.27 ± 0.542 vs. 0.439 ± 0.058 nmol urea/mg protein, p = 0.02). This was associated with a decrease in NO production, which was restored with BEC (4.54 ± 0.582 vs. 12.88 ± 0.432 μmol/mg, p < 0.01). IEM illustrates increased mitochondrial density in old myocytes (51.7 ± 1.8 vs. 69 ± 2.2 × 106/cm2, p < 0.01), potentially contributing to increased Arg-II abundance and activity. Immunohistochemistry revealed an organized pattern of mitochondria and Arg-II that appears disrupted in old myocytes. The FFR was significantly depressed in old myocytes (61.42 ± 16.04 vs. −5.15 ± 5.65%), while inhibition of Arg-II restored the FFR (−5.15 ± 5.65 vs. 70.98 ± 6.10%). NOS-2 is upregulated sixfold in old hearts contributing to increased production of reactive oxygen species which is attenuated with NOS-2 inhibition by 1400 W (4,735 ± 427 vs. 4,014 ± 314 RFU/min/mg protein, p = 0.005). Arg-II upregulation in aging rat hearts contributes to age-related decreased contractile function.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Balligand JL (1999) Regulation of cardiac beta-adrenergic response by nitric oxide. Cardiovasc Res 43:607–620

    Article  PubMed  CAS  Google Scholar 

  • Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O’Rourke B, Rodriguez ER, Huang PL, Lima JA, Berkowitz DE, Hare JM (2002) Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 416:337–339

    Article  PubMed  CAS  Google Scholar 

  • Berkowitz DE (2007) Myocyte nitroso-redox imbalance in sepsis: NO simple answer. Circ Res 100:1–4

    Article  PubMed  CAS  Google Scholar 

  • Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM (2003) Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 108:2000–2006

    Article  PubMed  CAS  Google Scholar 

  • Drew B, Leeuwenburgh C (2002) Aging and the role of reactive nitrogen species. Ann NY Acad Sci 959:66–81

    Article  PubMed  CAS  Google Scholar 

  • Gotoh T, Sonoki T, Nagasaki A, Terada K, Takiguchi M, Mori M (1996) Molecular cloning of cDNA for nonhepatic mitochondrial arginase (arginase II) and comparison of its induction with nitric oxide synthase in a murine macrophage-like cell line. FEBS Lett 395:119–122

    Article  PubMed  CAS  Google Scholar 

  • Hare JM (2003) Nitric oxide and excitation–contraction coupling. J Mol Cell Cardiol 35:719–729

    Article  PubMed  CAS  Google Scholar 

  • Hare JM (2004) Nitroso-redox balance in the cardiovascular system. N Engl J Med 351:2112–2114

    Article  PubMed  CAS  Google Scholar 

  • Hare JM, Givertz MM, Creager MA, Colucci WS (1998) Increased sensitivity to nitric oxide synthase inhibition in patients with heart failure: potentiation of beta-adrenergic inotropic responsiveness. Circulation 97:161–166

    Article  PubMed  CAS  Google Scholar 

  • Heinzel FR, Gres P, Boengler K, Duschin A, Konietzka I, Rassaf T, Snedovskaya J, Meyer S, Skyschally A, Kelm M, Heusch G, Schulz R (2008) Inducible nitric oxide synthase expression and cardiomyocyte dysfunction during sustained moderate ischemia in pigs. Circ Res 103:1120–1127

    Article  PubMed  CAS  Google Scholar 

  • Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS (2005) Protein S-nitrosylation: purview and parameters. Natl Rev Mol Cell Biol 6:150–166

    Article  CAS  Google Scholar 

  • Jung DH, Mo SH, Kim DH (2006) Calumenin, a multiple EF-hands Ca2+-binding protein, interacts with ryanodine receptor-1 in rabbit skeletal sarcoplasmic reticulum. Biochem Biophys Res Commun 343:34–42

    Article  PubMed  CAS  Google Scholar 

  • Khan SA, Hare JM (2003) The role of nitric oxide in the physiological regulation of Ca2+ cycling. Curr Opin Drug Discov Dev 6:658–666

    CAS  Google Scholar 

  • Khan SA, Skaf MW, Harrison RW, Lee K, Minhas KM, Kumar A, Fradley M, Shoukas AA, Berkowitz DE, Hare JM (2003) Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases. Circ Res 92:1322–1329

    Article  PubMed  CAS  Google Scholar 

  • Khan SA, Lee K, Minhas KM, Gonzalez DR, Raju SV, Tejani AD, Li D, Berkowitz DE, Hare JM (2004) Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation–contraction coupling. Proc Natl Acad Sci USA 101:15944–15948

    Article  PubMed  CAS  Google Scholar 

  • Kim JH, Bugaj LJ, Oh YJ, Bivalacqua TJ, Ryoo S, Soucy KG, Santhanam L, Webb A, Camara A, Sikka G, Nyhan D, Shoukas AA, Ilies M, Christianson DW, Champion HC, Berkowitz DE (2009a) Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J Appl Physiol 107:1249–1257

    Article  PubMed  CAS  Google Scholar 

  • Kim JH, Bugaj LJ, Oh YJ, Bivalacqua TJ, Ryoo S, Soucy KG, Santhanam L, Webb A, Camara A, Sikka G, Nyhan D, Shoukas AA, Ilies M, Christianson DW, Champion HC, Berkowitz DE (2009b) Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J Appl Physiol 107:1249–1257

    Article  PubMed  CAS  Google Scholar 

  • Krotova K, Patel JM, Block ER, Zharikov S (2010) Hypoxic upregulation of arginase II in human lung endothelial cells. Am J Physiol Cell Physiol 299:C1541–C1548

    Article  PubMed  CAS  Google Scholar 

  • Lee HY, Oh BH (2010) Aging and arterial stiffness. Circ J 74:2257–2262

    Article  PubMed  Google Scholar 

  • Morris SM Jr, Kepka-Lenhart D, Chen LC (1998) Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells. Am J Physiol 275:E740–E747

    PubMed  Google Scholar 

  • Musci G, Persichini T, Casadei M, Mazzone V, Venturini G, Polticelli F, Colasanti M (2006) Nitrosative/oxidative modifications and ageing. Mech Ageing Dev 127:544–551

    Article  PubMed  CAS  Google Scholar 

  • Pollock JS, Webb W, Callaway D, Sathyanarayana O’BrienW, Howdieshell TR (2001) Nitric oxide synthase isoform expression in a porcine model of granulation tissue formation. Surgery 129:341–350

    Article  PubMed  CAS  Google Scholar 

  • Rueckschloss U, Villmow M, Klockner U (2010) NADPH oxidase-derived superoxide impairs calcium transients and contraction in aged murine ventricular myocytes. Exp Gerontol 45:788–796

    Article  PubMed  CAS  Google Scholar 

  • Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G, Sohi J, Santhanam L, Soucy K, Tuday E, Baraban E, Ilies M, Gerstenblith G, Nyhan D, Shoukas A, Christianson DW, Alp NJ, Champion HC, Huso D, Berkowitz DE (2008) Endothelial arginase II: a novel target for the treatment of atherosclerosis. Circ Res 102:923–932

    Article  PubMed  CAS  Google Scholar 

  • Ryoo S, Bhunia A, Chang F, Shoukas A, Berkowitz DE, Romer LH (2011) OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream RhoA signaling. Atherosclerosis 214:279–287

    Article  PubMed  CAS  Google Scholar 

  • SalimuddinNagasaki, Nagasaki A, Gotoh T, Isobe H, Mori M (1999) Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide. Am J Physiol 277:E110–E117

    Google Scholar 

  • Santhanam L, Christianson DW, Nyhan D, Berkowitz DE (2008) Arginase and vascular aging. J Appl Physiol 105:1632–1642

    Article  PubMed  CAS  Google Scholar 

  • Stamler JS, Lamas S, Fang FC (2001) Nitrosylation: the prototypic redox-based signaling mechanism. Cell 106:675–683

    Article  PubMed  CAS  Google Scholar 

  • Steppan J, Ryoo S, Schuleri KH, Gregg C, Hasan RK, White AR, Bugaj LJ, Khan M, Santhanam L, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE (2006a) Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism. Proc Natl Acad Sci USA 103:4759–4764

    Article  PubMed  CAS  Google Scholar 

  • Steppan J, Ryoo S, Schuleri KH, Gregg C, Hasan RK, White AR, Bugaj LJ, Khan M, Santhanam L, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE (2006b) Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism. Proc Natl Acad Sci USA 103:4759–4764

    Article  PubMed  CAS  Google Scholar 

  • Umar S, van der Laarse A (2010) Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem 333:191–201

    Article  PubMed  CAS  Google Scholar 

  • Wessells RJ, Bodmer R (2006) Cardiac aging. Semin Cell Dev Biol

  • White AR, Ryoo S, Li D, Champion HC, Steppan J, Wang D, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE (2006) Knockdown of arginase I restores NO signaling in the vasculature of old rats. Hypertension 47:245–251

    Article  PubMed  CAS  Google Scholar 

  • Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC (1999) Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 96:657–662

    Article  PubMed  CAS  Google Scholar 

  • Yang B, Larson DF, Watson RR (2004) Modulation of iNOS activity in age-related cardiac dysfunction. Life Sci 75:655–667

    Article  PubMed  CAS  Google Scholar 

  • Zhang C, Hein TW, Wang W, Chang CI, Kuo L (2001) Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide-mediated vasodilatory function. FASEB J 15:1264–1266

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank all members of the Shoukas-Berkowitz lab for their support and assistance in this project. This work was supported by grant R01AG021523 from the NIH, grant CA01301 from the National Space Biomedical Research Institute through NASA, and NNH04ZUU005N from NASA.

Conflict of interest

None of the authors has any conflict of interest to report.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University Medicine, Tower 711, 600 N Wolfe St., Baltimore, MD, 21287, USA

    Mehnaz Khan, Jochen Steppan, Sungwoo Ryoo, Lakshmi Santhanam, Tal Berkowitz, Daniel Nyhan & Dan E. Berkowitz

  2. Department of Medicine, Johns Hopkins University Medicine, 600 N Wolfe St., Baltimore, MD, 21287, USA

    Karl Schuleri

  3. Department of Biomedical Engineering, Johns Hopkins University Medicine, 600 N Wolfe St., Baltimore, MD, 21287, USA

    Eric Tuday, Lukasz Bugaj, Artin A. Shoukas & Dan E. Berkowitz

Authors
  1. Mehnaz Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jochen Steppan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karl Schuleri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sungwoo Ryoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eric Tuday
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lukasz Bugaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lakshmi Santhanam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tal Berkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel Nyhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Artin A. Shoukas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dan E. Berkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dan E. Berkowitz.

Additional information

Communicated by Keith Phillip George.

M. Khan and J. Steppan contributed equally to the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khan, M., Steppan, J., Schuleri, K. et al. Upregulation of arginase-II contributes to decreased age-related myocardial contractile reserve. Eur J Appl Physiol 112, 2933–2941 (2012). https://doi.org/10.1007/s00421-011-2257-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00421-011-2257-9

Keywords

Search

Navigation