ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy
ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy
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DOI：
10.1016/j.lfs.2012.02.006
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发表时间：
2012-10-15
期刊：
影响因子：
6.1
通讯作者：
Emoto, Noriaki
中科院分区：
文献类型：
--
作者：
Adiarto, Suko;Heiden, Susi;Emoto, Noriaki
目的：高血压患者发生心脏肥大和纤维化，僵硬度增加，收缩功能障碍和灌注改变。血管紧张素II（AngII）是促进这种病理的重要因素。AngII的作用部分由内皮素-1（ET-1）和转化生长因子-β介导。这些通路的确切特征和所涉及的细胞间通讯尚不清楚。在这项研究中，我们探讨了内皮细胞衍生的ET-1在血管紧张素II诱导的心脏纤维化和hypertrophy.Main方法的发展中的作用：我们使用了小鼠血管内皮细胞特异性ET-1缺乏症（VEETKO）和他们的野生型同窝仔（WT）。使用皮下微型泵向小鼠输注AngII（3.2mg/kg/天，n = 12）或载体（0.15mol/L NaCl和1 mmol/L乙酸，n = 5）一周。心脏用苏木精伊红和马森三色染色用于组织学。心脏基因表达和蛋白质丰度通过北方印迹，真实的时间PCR和Western Blot.Key发现：血管紧张素II诱导的心脏肥大，间质和血管周围纤维化在VEETKO小鼠相比，WT不太明显。两种基因型的血压升高相似。结缔组织生长因子、肿瘤生长因子-β、胶原蛋白I和III的表达对AngII的反应需要内皮ET-1。内皮ET-1也是蛋白激酶C δ丰度和ERK 1/2激活升高所必需的。然而，血管紧张素II诱导的PKC β 2丰度升高是ET-1 independent.Significance：这项研究强调了血管内皮素1在血管紧张素II诱导的心脏肥大和纤维化过程中的意义，独立于血压。因此，内皮ET-1是一个可能的药理学靶点。(c)2012 Elsevier Inc. All rights reserved.
Aims: Hypertensive patients develop cardiac hypertrophy and fibrosis with increased stiffness, contractile deficit and altered perfusion. Angiotensin II (AngII) is an important factor in the promotion of this pathology. The effects of AngII are partly mediated by endothelin-1 (ET-1) and transforming growth factor-beta. The exact feature of these pathways and the intercellular communications involved remain unclear. In this study, we explored the role of endothelial cell-derived ET-1 in the development of AngII-induced cardiac fibrosis and hypertrophy.Main methods: We used mice with vascular endothelial cell specific ET-1 deficiency (VEETKO) and their wild type littermates (WT). Mice were infused for one week with AngII (3.2 mg/kg/day, n = 12) or vehicle (0.15 mol/L NaCl and 1 mmol/L acetic acid, n = 5), using subcutaneous mini-pumps. Hearts were stained with hematoxylin eosin and masson's trichrome for histology. Cardiac gene expression and protein abundance were measured by Northern Blot, real time PCR and Western Blot.Key findings: AngII-induced cardiac hypertrophy, interstitial and perivascular fibrosis were less pronounced in VEETKO mice compared to WT. Blood pressure increased similarly in both genotypes. Expression of connective tissue growth factor, tumor growth factor-beta, collagen I and III in response to AngII required endothelial ET-1. Endothelial ET-1 was also necessary to the elevation in protein kinase C delta abundance and ERK1/2 activation. AngII-induced elevation in PKC epsilon abundance was however ET-1 independent.Significance: This study underscores the significance of ET-1 from the vasculature in the process of AngII-induced cardiac hypertrophy and fibrosis, independently from blood pressure. Endothelial ET-1 represents therefore a possible pharmacological target. (c) 2012 Elsevier Inc. All rights reserved.