Upregulation of arginase-II contributes to decreased age-related myocardial contractile reserve.
Upregulation of arginase-II contributes to decreased age-related myocardial contractile reserve.
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精氨酸酶-II 的上调导致与年龄相关的心肌收缩储备下降。
DOI：
10.1007/s00421-011-2257-9
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发表时间：
2012
影响因子：
3
通讯作者：
Berkowitz,DanE
中科院分区：
文献类型：
--
作者：
Khan,Mehnaz;Steppan,Jochen;Schuleri,KarlH;Schuleri,Karl;Ryoo,Sungwoo;Tuday,Eric;Bugaj,Lukasz;Santhanam,Lakshmi;Berkowitz,Tal;Nyhan,Daniel;Shoukas,ArtinA;Berkowitz,DanE
精氨酸酶-II (Arg-II) 相互调节一氧化氮合酶 (NOS) 并抵消基础心肌收缩力。此外，心肌NOS活性降低或缺失与心肌收缩储备下降相关。因此，我们推测 Arg-II 的上调可能是与年龄相关的心肌收缩力下降的部分原因。我们研究了老年（22 个月）和年轻（3 个月）大鼠心脏和肌细胞中存在和不存在精氨酸酶抑制剂 S-(2-硼乙基)-l-半胱氨酸 (BEC) 的情况下的精氨酸酶活性/表达、NOS 表达、NO 产生。 Arg-II 和 NOS 的空间限制通过免疫电子显微成像 (IEM) 和免疫组织化学研究来确定。我们测试了 BEC 对肌细胞力频率响应 (FFR) 以及 NOS 丰度和活性的影响。老年心脏中的精氨酸酶活性和 Arg-II 表达增加（2.27 ± 0.542 vs. 0.439 ± 0.058 nmol 尿素/mg 蛋白，p= 0.02）。这与 NO 产生的减少有关，而 BEC 可以恢复 NO 产生的减少（4.54 ± 0.582 vs. 12.88 ± 0.432 μmol/mg，p < 0.01）。 IEM 表明老年肌细胞中线粒体密度增加（51.7 ± 1.8 vs. 69 ± 2.2 × 106/cm2，p < 0.01），可能有助于增加 Arg-II 丰度和活性。免疫组织化学揭示了衰老心肌细胞中线粒体和 Arg-II 的组织模式似乎被破坏。老肌细胞的 FFR 显着降低（61.42 ± 16.04 vs. -5.15 ± 5.65%），而 Arg-II 的抑制则恢复了 FFR（-5.15 ± 5.65 vs. 70.98 ± 6.10%）。 NOS-2 在老年心脏中上调六倍，导致活性氧产生增加，NOS-2 抑制 1400 W 会减弱活性氧的产生（4,735 ± 427 vs. 4,014 ± 314 RFU/min/mg 蛋白质，p= 0.005）。衰老大鼠心脏中 Arg-II 的上调导致与年龄相关的收缩功能下降。
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 inhibitorS-(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.