Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles.
Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles.
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急性和慢性高血糖引起的JIP1/JNK介导的视网膜动脉内皮血管扩张剂功能障碍。
DOI：
10.1167/iovs.16-19990
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发表时间：
2016-08-01
影响因子：
4.4
通讯作者：
Kuo L
中科院分区：
文献类型：
--
作者：
Hein TW;Xu W;Xu X;Kuo L
高血压是糖尿病的标志，与视网膜炎症和内皮依赖性一氧化氮（NO）介导的视网膜小动脉扩张受损相关。然而，这种内皮血管舒张功能减弱的分子机制仍不清楚。我们研究了急性和慢性高血糖暴露过程中，炎症应激激活的激酶，c-Jun N-末端激酶（JNK）和p38是否有助于视网膜小动脉功能障碍。从链脲佐菌素诱导的糖尿病猪（2周;慢性高血糖，471 ± 23 mg/dL）或年龄匹配的对照猪（正常，79 ± 5 mg/dL）分离视网膜小动脉，然后插管并加压用于血管反应性研究。对于急性高血糖研究，将来自非糖尿病猪的血管腔内暴露于高葡萄糖（25 mM ~ 450 mg/dL）2小时，并将正常葡萄糖（5 mM ~ 90 mg/dL）用作对照。血管内皮依赖性血管舒张缓激肽减少后，暴露于急性或慢性高血糖症以类似的方式。NO合成酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）的管理几乎取消了血管舒张无论是在控制（正常血糖和正常血糖）或高血糖（急性和慢性）血管。用JNK抑制剂SP 600125或JNK相互作用蛋白-1（JIP 1）抑制剂BI-78 D3治疗急性或慢性高血糖血管，而不是p38抑制剂SB 203580，以L-NAME敏感的方式保留缓激肽诱导的扩张。相反，硝普钠的非内皮依赖性血管舒张不受急性或慢性高血糖的影响。急性或慢性高血糖时视网膜小动脉中JIP 1/JNK信号的激活导致内皮依赖性NO介导的血管扩张的选择性损伤血管JNK通路的治疗靶点可能改善早期糖尿病视网膜内皮血管舒张功能。
Hyperglycemia, a hallmark of diabetes mellitus, is associated with retinal inflammation and impairment of endothelium-dependent nitric oxide (NO)–mediated dilation of retinal arterioles. However, molecular mechanisms involved in this diminished endothelial vasodilator function remain unclear. We examined whether inflammatory stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38, contribute to retinal arteriolar dysfunction during exposure to acute and chronic hyperglycemia. Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks; chronic hyperglycemia, 471 ± 23 mg/dL) or age-matched control pigs (euglycemia, 79 ± 5 mg/dL), and then cannulated and pressurized for vasoreactivity study. For acute hyperglycemia study, vessels from nondiabetic pigs were exposed intraluminally to high glucose (25 mM ≈ 450 mg/dL) for 2 hours, and normal glucose (5 mM ≈ 90 mg/dL) served as the control. Endothelium-dependent vasodilation to bradykinin was reduced in a similar manner after exposure to acute or chronic hyperglycemia. Administration of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) nearly abolished vasodilations either in control (euglycemia and normal glucose) or hyperglycemic (acute and chronic) vessels. Treatment of either acute or chronic hyperglycemic vessels with JNK inhibitor SP600125 or JNK-interacting protein-1 (JIP1) inhibitor BI-78D3, but not p38 inhibitor SB203580, preserved bradykinin-induced dilation in an L-NAME–sensitive manner. By contrast, endothelium-independent vasodilation to sodium nitroprusside was unaffected by acute or chronic hyperglycemia. Activation of JIP1/JNK signaling in retinal arterioles during exposure to acute or chronic hyperglycemia leads to selective impairment of endothelium-dependent NO-mediated dilation. Therapeutic targeting of the vascular JNK pathway may improve retinal endothelial vasodilator function during early diabetes.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
37.8
作者：
Ho, FM;Liu, SH;Lin-Shiau, SY
通讯作者：
Lin-Shiau, SY
影响因子：
4.1
作者：
Garhöfer, G;Zawinka, C;Dorner, GT
通讯作者：
Dorner, GT
影响因子：
4.4
作者：
Hein, Travis W.;Rosa, Robert H., Jr.;Kuo, Lih
通讯作者：
Kuo, Lih
影响因子：
4.4
作者：
Hammer, Martin;Heller, Tabitha;Mueller, Ulrich-Alfons
通讯作者：
Mueller, Ulrich-Alfons