Advanced glycation end products activate a chymase-dependent angiotensin II-generating pathway in diabetic complications
Advanced glycation end products activate a chymase-dependent angiotensin II-generating pathway in diabetic complications
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DOI：
10.1161/circulationaha.105.575589
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发表时间：
2006-03-14
期刊：
影响因子：
37.8
通讯作者：
Lan, HY
中科院分区：
文献类型：
--
作者：
Koka, V;Wang, WS;Lan, HY
背景-血管紧张素II是糖尿病相关血管疾病的关键介质。目前认为，在高血压和糖尿病中，除了血管紧张素转换酶外，糜酶是一种重要的血管紧张素II生成酶。然而，在diabetes.Methods和结果-在这里，我们报告，糜酶的诱导机制上调糖尿病患者的冠状动脉和肾动脉的免疫组化。血管糜酶的上调与晚期糖基化终产物（AGEs）的沉积、AGEs受体表达的增加和ERK 1/2 MAP激酶的激活有关。在体外，AGEs可通过RAGE-ERK 1/2 MAP激酶依赖性机制诱导人血管平滑肌细胞中糜酶表达和糜酶依赖性血管紧张素II产生。这通过用中和性ERK抗体和ERK 1/2抑制剂阻断AGE诱导的血管糜酶表达以及通过显性负性ERK 1/2的过表达来证实。与血管紧张素转换酶相比，糜酶对AGEs诱导的血管紧张素II的产生起主要作用（> 70%，P < 0.01）。此外，AGEs诱导的血管紧张素II的生产被阻断的抗ERK抗体和ERK 1/2 MAP激酶activity.Conclusions - AGEs，糖尿病的标志，诱导糜酶通过RAGE-ERK 1/2 MAP激酶途径的抑制。糜酶是糖尿病血管紧张素II生成的重要途径之一，在糖尿病血管病变中起重要作用。
Background - Angiotensin II is a key mediator of diabetes-related vascular disease. It is now recognized that in addition to angiotensin-converting enzyme, chymase is an important alternative angiotensin II - generating enzyme in hypertension and diabetes. However, the mechanism of induction of chymase in diabetes remains unknown.Methods and Results - Here, we report that chymase is upregulated in coronary and renal arteries in patients with diabetes by immunohistochemistry. Upregulation of vascular chymase is associated with deposition of advanced glycation end products (AGEs), an increase in expression of the receptor for AGEs ( RAGE), and activation of ERK1/2 MAP kinase. In vitro, AGEs can induce chymase expression and chymase-dependent angiotensin II generation in human vascular smooth muscle cells via the RAGE-ERK1/2 MAP kinase - dependent mechanism. This is confirmed by blockade of AGE-induced vascular chymase expression with a neutralizing RAGE antibody and an inhibitor to ERK1/2 and by overexpression of the dominant negative ERK1/2. Compared with angiotensin-converting enzyme, chymase contributes to the majority of angiotensin II production (> 70%, P < 0.01) in response to AGEs. Furthermore, AGE-induced angiotensin II production is blocked by the anti-RAGE antibody and by inhibition of ERK1/2 MAP kinase activities.Conclusions - AGEs, a hallmark of diabetes, induce chymase via the RAGE-ERK1/2 MAP kinase pathway. Chymase initiates an important alternative angiotensin II - generating pathway in diabetes and may play a critical role in diabetic vascular disease.