title: Upregulation of arginase-II contributes to decreased age-related myocardial contractile reserve.
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 × 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 ± 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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University Medicine, Tower 711, 600 N Wolfe St., Baltimore, MD 21287, USA.
authors.forename: Mehnaz
authors.initials: M
authors.lastname: Khan
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.forename: Karl H
authors.initials: KH
authors.lastname: Schuleri
authors.forename: Karl
authors.initials: K
authors.lastname: Schuleri
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Ryoo
authors.forename: Eric
authors.initials: E
authors.lastname: Tuday
authors.forename: Lukasz
authors.initials: L
authors.lastname: Bugaj
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.forename: Tal
authors.initials: T
authors.lastname: Berkowitz
authors.forename: Daniel
authors.initials: D
authors.lastname: Nyhan
authors.forename: Artin A
authors.initials: AA
authors.lastname: Shoukas
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006331:Heart Diseases / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D016253:Microscopy, Immunoelectron; D008929:Mitochondria, Heart / Q000201:enzymology / Q000648:ultrastructure; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: C425062:(2-boronoethyl)-cysteine; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C113162:Arg2 protein, rat; D001119:Arginase