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

作者：Khan Mehnaz; Steppan Jochen; Schuleri Karl; Ryoo Sungwoo; Tuday Eric; Bugaj Lukasz; Santhanam Lakshmi; Berkowitz Tal; Nyhan Daniel; Shoukas Artin A; Berkowitz Dan E^*

来源：European Journal of Applied Physiology, 2012, 112(8): 2933-2941.

DOI：10.1007/s00421-011-2257-9

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

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 +/- A 0.542 vs. 0.439 +/- A 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 +/- A 0.582 vs. 12.88 +/- A 0.432 mu mol/mg, p < 0.01). IEM illustrates increased mitochondrial density in old myocytes (51.7 +/- A 1.8 vs. 69 +/- A 2.2 x 10(6)/cm(2), 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 +/- A 16.04 vs. -5.15 +/- A 5.65%), while inhibition of Arg-II restored the FFR (-5.15 +/- A 5.65 vs. 70.98 +/- A 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 +/- A 427 vs. 4,014 +/- A 314 RFU/min/mg protein, p = 0.005). Arg-II upregulation in aging rat hearts contributes to age-related decreased contractile function.

• 出版日期2012-8