Toque Haroldo A, Nunes Kenia P, Yao Lin, Xu Zhimin, Kondrikov Dmitry, Su Yunchao, Webb R Clinton, Caldwell Ruth B, Caldwell R William
Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia, United States of America.
PLoS One. 2013 Aug 19;8(8):e72277. doi: 10.1371/journal.pone.0072277. eCollection 2013.
Elevated arginase (Arg) activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO) synthase (NOS) and NO production. Akita mice, a genetic non-obese type 1 diabetes model, recapitulate human diabetes. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC) from Akita mice.
Endothelium-dependent relaxation, Arg and NOS activity, and protein expression levels of Arg and constitutive NOS were assessed in aortas and CC from Akita and non-diabetic wild type (WT) mice at 4, 12 and 24 wks of age. Systolic blood pressure (SBP) was assessed by tail cuff. In aorta and CC, Akita mice exhibited a progressive impairment of vascular endothelial and nitrergic function increased Arg activity and expression (Arg1 in aorta and both Arg1 and Arg2 in CC) compared with that of age-matched WT mice. Treatment of aorta and CC from Akita mice with an Arg inhibitor (BEC or ABH) reduced diabetes-induced elevation of Arg activity and restored endothelial and nitrergic function. Reduced levels of phospho-eNOS at Ser(1177) (in aorta and CC) and nNOS expression (in CC) were observed in Akita mice at 12 and 24 wks. Akita mice also had decreased NOS activity in aorta and CC at 12 and 24 wks that was restored by BEC treatment. Further, Akita mice exhibited moderately increased SBP at 24 wks and increased sensitivity to PE-induced contractions in aorta and sympathetic nerve stimulation in CC at 12 and 24 wks.
Over 24 wks of diabetes in Akita mice, both aortic and cavernosal tissues exhibited increased Arg activity/expression, contributing to impaired endothelial and nitrergic function and reduced NO production. Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse.
据报道，精氨酸酶（Arg）活性升高与糖尿病诱导的血管内皮功能障碍有关。它会减少一氧化氮（NO）合酶（NOS）可利用的L-精氨酸，进而降低NO的生成。秋田小鼠是一种遗传性非肥胖1型糖尿病模型，可模拟人类糖尿病。我们确定了Arg在秋田小鼠主动脉和海绵体（CC）糖尿病相关内皮功能障碍病程中的作用。
对4周、12周和24周龄的秋田小鼠和非糖尿病野生型（WT）小鼠的主动脉和CC进行评估，检测内皮依赖性舒张、Arg和NOS活性，以及Arg和组成型NOS的蛋白表达水平。通过尾套法评估收缩压（SBP）。与年龄匹配的WT小鼠相比，秋田小鼠的主动脉和CC中血管内皮和一氧化氮能功能逐渐受损，Arg活性和表达增加（主动脉中为Arg1，CC中为Arg1和Arg2）。用Arg抑制剂（BEC或ABH）处理秋田小鼠的主动脉和CC，可降低糖尿病诱导的Arg活性升高，并恢复内皮和一氧化氮能功能。在12周和24周时，秋田小鼠的主动脉和CC中Ser(1177)位点的磷酸化eNOS水平降低（主动脉和CC中），nNOS表达降低（CC中）。在12周和24周时，秋田小鼠主动脉和CC中的NOS活性也降低，BEC处理可使其恢复。此外，秋田小鼠在24周时SBP适度升高，在12周和24周时对主动脉中PE诱导的收缩和CC中交感神经刺激的敏感性增加。
在秋田小鼠中，超过24周的糖尿病病程中，主动脉和海绵体组织的Arg活性/表达均增加，导致内皮和一氧化氮能功能受损以及NO生成减少。我们的研究结果表明，Arg活性参与了秋田小鼠糖尿病诱导的血管功能损害。
