Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.
Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.
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DOI：
10.1161/hypertensionaha.115.05344
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发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
Eguchi S
中科院分区：
文献类型：
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作者：
Takayanagi T;Kawai T;Forrester SJ;Obama T;Tsuji T;Fukuda Y;Elliott KJ;Tilley DG;Davisson RL;Park JY;Eguchi S
血管紧张素II(AngII)升高血压和增强终末器官损伤的机制似乎是不同的。然而，Angii特异性地介导血管重构的信号转导通路仍不完整，如中膜肥厚和血管周围纤维化。我们先前已经证明，Angii诱导的表皮生长因子受体(EGFR)反式激活是由金属蛋白酶ADAM17介导的，该信号是血管平滑肌细胞肥大所必需的，但不是Angii反应的收缩信号所必需的。最近的研究表明内质网(ER)应激与高血压有关。有趣的是，EGFR能够诱导内质网应激。本研究的目的是验证这样的假设，即EGFR和内质网应激的激活是血管重塑的关键成分，而不是血管紧张素转换酶诱导的高血压所必需的。在给予或不给予EGFR抑制剂erlotinib或ER伴侣4-苯丁酸酯治疗的情况下，小鼠接受血管紧张素转换酶II治疗2周。血管紧张素转换酶抑制剂可引起心脏、肾脏和主动脉血管中层肥厚，心脏和肾脏血管周围纤维化，心肌肥厚和高血压。厄洛替尼和4-苯丁酸酯治疗可减轻血管重塑和心肌肥厚，但不能减轻高血压。此外，血管紧张素转换酶抑制剂可增强血管中ADAM17的表达、EGFR的激活和ER/氧化应激，这些在厄洛替尼治疗和4-苯丁酸酯治疗的小鼠中都被减弱。血管内皮细胞ADAM17的诱导和血管内皮细胞EGFR的激活也可通过抑制EGFR或内质网应激来阻止。总之，血管紧张素转换酶通过EGFR激活和内质网应激诱导血管重塑，其信号机制涉及ADAM17的诱导，不依赖于高血压。
The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage appear to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by metalloprotease ADAM17, and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with Erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells was also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension.