Activated Rho kinase mediates diabetes-induced elevation of vascular arginase activation and contributes to impaired corpora cavernosa relaxation: possible involvement of p38 MAPK activation.
Activated Rho kinase mediates diabetes-induced elevation of vascular arginase activation and contributes to impaired corpora cavernosa relaxation: possible involvement of p38 MAPK activation.
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DOI：
10.1111/jsm.12134
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Caldwell RW
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文献类型：
--
作者：
Toque HA;Nunes KP;Yao L;Liao JK;Webb RC;Caldwell RB;Caldwell RW
激活的RhoA/Rho激酶（ROCK）与糖尿病诱导的勃起功能障碍有关。早期的研究已经证明ROCK通路参与内皮细胞中凝血酶的活化。然而，ROCK在阴茎中激活的信号通路仍不清楚。我们测试了ROCK和p38 MAPK是否参与糖尿病患者的肌酶活性升高和随后的海绵体（CC）松弛受损。在链脲佐菌素诱导糖尿病后8周，在来自非糖尿病野生型（WT）、糖尿病（D）WT（WT + D）、部分ROCK 2+/−敲除（KO）和ROCK 2+/− KO + D小鼠的CC组织中评估血管功能研究、激酶活性测定以及RhoA、ROCK、磷酸化p38 MAPK、p38 MAPK、磷酸化MYPT-1 Thr 850、MYPT-1和激酶水平的蛋白表达。检测RhoA、ROCK 1和2的表达、MYPT-1 Thr 850和p38 MAPK的磷酸化、β-内酰胺酶活性/表达、CC的内皮依赖性和氮依赖性舒张。糖尿病显著降低了对内皮依赖性乙酰胆碱（WT + D：Emax; 61 ± 4% vs. WT：Emax; 75 ± 2%）和氮能神经刺激的最大舒张（Emax）。这些作用与WT糖尿病CC中活性RhoA、ROCK 2、磷酸化MYPT-1 Thr 850、磷酸化p38 MAPK、磷酸化酶II的表达增加和磷酸化酶活性（1.6倍）相关。然而，在杂合子ROCK 2+/− KO + D小鼠中，WT + D小鼠的CC中不存在乙酰胆碱（Emax：80 ± 5%）的这种损伤，并且氮能神经诱导的松弛减弱。ROCK 2+/-KO + D小鼠的CC显示出更低的ROCK活性，没有表现出p38 MAPK激活，并且精氨酸酶活性和精氨酸酶II表达降低。这些发现表明ROCK 2介导糖尿病诱导的葡萄糖氧化酶活性升高。此外，WT糖尿病CC预处理与抑制剂的乙酰胆碱酯酶（ABH）或p38 MAPK（SB 203580）部分防止损害乙酰胆碱和氮能神经诱导的松弛和升高的乙酰胆碱酯酶活性。ROCK 2、p38 MAPK和p38激酶在糖尿病引起的CC松弛损伤中起关键作用。
Activated RhoA/Rho kinase (ROCK) has been implicated in diabetes-induced erectile dysfunction. Earlier studies have demonstrated involvement of ROCK pathway in the activation of arginase in endothelial cells. However, signaling pathways activated by ROCK in the penis remain unclear. We tested whether ROCK and p38 MAPK are involved in the elevation of arginase activity and subsequent impairment of corpora cavernosal (CC) relaxation in diabetes. Eight weeks after streptozotocin-induced diabetes, vascular functional studies, arginase activity assay, and protein expression of RhoA, ROCK, phospho-p38 MAPK, p38 MAPK, phospho-MYPT-1Thr850, MYPT-1 and arginase levels were assessed in CC tissues from nondiabetic wild type (WT), diabetic (D) WT (WT + D), partial ROCK 2+/− knockout (KO), and ROCK 2+/− KO + D mice. The expression of RhoA, ROCK 1 and 2, phosphorylation of MYPT-1Thr850 and p38 MAPK, arginase activity/expression, endothelial- and nitrergic-dependent relaxation of CC was assayed. Diabetes significantly reduced maximum relaxation (Emax) to both endothelium-dependent acetylcholine (WT + D: Emax; 61 ± 4% vs. WT: Emax; 75 ± 2%) and nitrergic nerve stimulation. These effects were associated with increased expression of active RhoA, ROCK 2, phospho-MYPT-1Thr850, phospho-p38 MAPK, arginase II, and activity of corporal arginase (1.6-fold) in WT diabetic CC. However, this impairment in CC of WT + D mice was absent in heterozygous ROCK 2+/− KO + D mice for acetylcholine (Emax: 80 ± 5%) and attenuated for nitrergic nerve-induced relaxation. CC of ROCK 2+/− KO + D mice showed much less ROCK activity, did not exhibit p38 MAPK activation, and had reduced arginase activity and arginase II expression. These findings indicate that ROCK 2 mediates diabetes-induced elevation of arginase activity. Additionally, pretreatment of WT diabetic CC with inhibitors of arginase (ABH) or p38 MAPK (SB203580) partially prevented impairment of ACh- and nitrergic nerve-induced relaxation and elevation of arginase activity. ROCK 2, p38 MAPK and arginase play key roles in diabetes-induced impairment of CC relaxation.
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影响因子：
4.8
作者：
Kureishi, Y;Kobayashi, S;Ito, M
通讯作者：
Ito, M
DOI：
10.1152/ajpheart.00560.2010
发表时间：
2011-04-01
影响因子：
4.8
作者：
Gronros, Julia;Jung, Christian;Pernow, John
通讯作者：
Pernow, John
影响因子：
4.8
作者：
Amano, M;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
DOI：
10.1073/pnas.0400520101
发表时间：
2004-06-15
影响因子：
11.1
作者：
Bivalacqua, TJ;Champion, HC;Kadowitz, PJ
通讯作者：
Kadowitz, PJ
影响因子：
4.4
作者：
Du, Yunpeng;Tang, Jie;Kern, Timothy S.
通讯作者：
Kern, Timothy S.