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

Mehnaz Khan, Jochen Steppan, Karl Schuleri, Sungwoo Ryoo, Eric Tuday, Lukasz Bugaj, Lakshmi Santhanam, Tal Berkowitz, Daniel Nyhan, Artin A. Shoukas, Dan E. Berkowitz

Research output: Contribution to journalArticle

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 upregula-tion 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 × 10 6/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.

Original languageEnglish (US)
Pages (from-to)2933-2941
Number of pages9
JournalEuropean Journal of Applied Physiology
Volume112
Issue number8
DOIs
StatePublished - Aug 2012

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Keywords

  • Aging
  • Arginase
  • Cardiovascular system
  • Heart
  • Myocyte
  • NOS
  • Nitric oxide synthase
  • Redox balance

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Public Health, Environmental and Occupational Health
  • Physiology (medical)

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