کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8268201 | 1534953 | 2016 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Citron Rho-interacting kinase mediates arsenite-induced decrease in endothelial nitric oxide synthase activity by increasing phosphorylation at threonine 497: Mechanism underlying arsenite-induced vascular dysfunction
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کلمات کلیدی
PP1S1PRpKaeNOSPRKPP2APKCPSSIBMXAMPK3-isobutyl-1-methylxanthine - 3-ایزوبوتیل-1-متیلکسانتینAMP-activated protein kinase - AMP-پروتئین کیناز فعال شده استROS - ROSarsenite - آرسنیتendothelial NO synthase - اندوتلیال NO سنتازVascular disease - بیماری عروقRho - روEndothelial cells - سلولهای اندوتلیالendothelial nitric oxide synthase - سنتاز اکسید نیتریک اندوتلیالdominant negative - غالب منفی استPhosphorylation - فسفریلاسیونNitric oxide - نیتریک اکسیدprotein phosphatase 1 - پروتئین فسفاتاز 1protein phosphatase 2A - پروتئین فسفاتاز 2Aprotein kinase A - پروتئین کیناز AProtein kinase C - پروتئین کیناز سیRho-associated protein kinase - پروتئین کیناز وابسته به RhoReactive oxygen species - گونههای فعال اکسیژنsphingosine-1-phosphate receptor - گیرنده اسپینگوزین-1-فسفاتRock - یا راک
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
We reported that arsenite causes an acute decrease in nitric oxide (NO) production by increasing phosphorylation of endothelial NO synthase at threonine 497 (eNOS-Thr497); however, the detailed mechanism has not yet been clarified. Here, we investigated the kinase involving in arsenite-stimulated eNOS-Thr497 phosphorylation. Although treatment with H-89, a known protein kinase A (PKA) inhibitor, inhibited arsenite-stimulated eNOS-Thr497 phosphorylation, no inhibition was found in cells treated with other PKA inhibitors, including Rp-8-Br-cAMPS or PKI. Based on previous reports, we also tested whether RhoA mediates arsenite-stimulated eNOS-Thr497 phosphorylation and found that arsenite causes an acute increase in RhoA activity. Ectopic expression of dominant negative (DN)-RhoA significantly reversed arsenite-stimulated eNOS-Thr497 phosphorylation. An in vitro phosphorylation assay also revealed that the well-known Rho effectors, Rho-associated protein kinase 1/2 (ROCK1/2), directly phosphorylate eNOS-Thr497. Y27632, a selective ROCK inhibitor, reversed arsenite-stimulated eNOS-Thr497 phosphorylation. However, overexpression of a small interfering RNA (siRNA) against ROCK1/2 or DN-ROCK did not reverse arsenite-stimulated eNOS-Thr497 phosphorylation, thereby providing no conclusive evidence of a role for ROCK1/2. Knockdown of PKC-related protein kinase 1/2, another Rho effector, also did not reverse arsenite-stimulated eNOS-Thr497 phosphorylation. In contrast, we found that transfection with an siRNA against citron Rho-interacting kinase (CRIK), the other downstream effector of Rho, significantly reversed the arsenite-induced eNOS-Thr497 phosphorylation that was accompanied by restoration of eNOS enzymatic activity repressed by arsenite. Moreover, CRIK directly phosphorylated eNOS-Thr497in vitro. Finally, we also found that arsenite increased eNOS-Thr497 phosphorylation and decreased acetylcholine-induced vessel relaxation in rat aortas. In conclusion, we demonstrate that arsenite acutely inhibits eNOS enzymatic activity and vessel relaxation in part by increasing the RhoA/CRIK/eNOS-Thr497 phosphorylation signaling axis, which provides a molecular mechanism underlying arsenite-induced impaired vascular diseases.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 90, January 2016, Pages 133-144
Journal: Free Radical Biology and Medicine - Volume 90, January 2016, Pages 133-144
نویسندگان
Jungwon Seo, Du-Hyong Cho, Hyeon-Ju Lee, Min-Sun Sung, Jee Young Lee, Kyung-Jong Won, Jung-Hyun Park, Inho Jo,