Axl mediates vascular remodeling induced by deoxycorticosterone acetate-salt hypertension
Axl mediates vascular remodeling induced by deoxycorticosterone acetate-salt hypertension
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DOI：
10.1161/hypertensionaha.107.096289
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发表时间：
2007-12-01
期刊：
影响因子：
8.3
通讯作者：
Berk, Bradford C.
中科院分区：
文献类型：
--
作者：
Korshunov, Vyacheslav A.;Daul, Matthew;Berk, Bradford C.
Ax 1是一种受体酪氨酸激酶，最近被鉴定为盐敏感性高血压遗传模型（Sabra大鼠）的新候选基因。我们的研究小组首次报道了Ax 1在血管损伤后的重塑中起着重要作用。在这里，我们研究了Ax 1在醋酸脱氧皮质酮（DOCA）-盐模型中高血压发病机制中的作用。在Ax 1野生型（Ax 1（+/+））小鼠和Ax 1缺陷型（Ax 1（-/-））小鼠中通过单侧肾切除和DOCA-盐诱导高血压6周。对照组行单侧肾切除术，自由饮用自来水和常规食物。DOCA盐治疗1周后两种基因型的收缩压均增加25 mm Hg。在6周时，Ax 1（+/+）DOCA小鼠的收缩压仍然显著升高，而Ax 1（-/-）DOCA小鼠的收缩压水平与对照组相同。DOCA盐增加相对肾脏重量和肾小球肥大40%，与对照组相比，在两种基因型。与收缩压水平一致，与Ax 1（+/+）对照组相比，Ax 1（+/+）DOCA小鼠的内皮依赖性血管舒张受损，而Ax 1（-/-）DOCA小鼠的舒张反应与Ax 1（-/-）对照组相似。此外，与Ax 1（+/+）DOCA小鼠相比，Ax 1（-/-）DOCA小鼠中的内皮非依赖性血管舒张改善。与Ax 1（+/+）DOCA小鼠相比，Ax 1（-/-）DOCA小鼠动脉中的硝基酪氨酸和磷酸化Akt免疫反应性显著降低。与Ax 1（-/-）DOCA小鼠相比，Ax 1（+/+）DOCA小鼠的肠系膜动脉重塑指数（中膜：管腔比）显著增加。最后，Ax 1（-/-）DOCA小鼠血管凋亡增加表明Ax 1依赖性高血压的可能机制。这些数据加强了Ax 1在盐敏感性高血压中的致病作用。（高血压。2007; 50：1057- 1062.）。
Ax1, a receptor tyrosine kinase, was recently identified as a novel candidate gene in a genetic model of salt- sensitive hypertension (Sabra rat). Our group first reported that Ax1 plays a significant role in vascular remodeling in response to injury. Here we investigated the role of Ax1 in the pathogenesis of hypertension in a deoxycorticosterone acetate ( DOCA) - salt model. Hypertension was induced in Ax1 wild- type (Ax1(+/+)) mice and Ax1-deficient ( Ax1(-/-)) mice by uninephrectomy and DOCA- salt for 6 weeks. Controls were uninephrectomized and received tap water and regular chow ad libitum. DOCA-salt treatment increased systolic blood pressure by 25 mm Hg in both genotypes after 1 week. Systolic blood pressure remained significantly elevated in Ax1(+/+) DOCA, whereas systolic blood pressure levels in Ax1(-/-) DOCA mice were the same as controls at 6 weeks. DOCA-salt increased relative kidney weight and glomerular hypertrophy by 40% compared with controls in both genotypes. Consistent with levels of systolic blood pressure, endothelium- dependent vasorelaxation was impaired in Ax1(+/+) DOCA mice compared with Ax1(+/+) controls, whereas in Ax1(-/-) DOCA mice relaxation responses were similar to Ax1(-/-) controls. In addition, endothelium- independent vasorelaxation was improved in Ax1(-/-) DOCA mice compared with Ax1(+/+) DOCA mice. Nitrotyrosine and phospho- Akt immunoreactivity was significantly reduced in arteries from Ax1(-/-) DOCA mice compared with Ax1(+/+) DOCA mice. The remodeling index of the mesenteric artery ( media: lumen ratio) was significantly increased in Ax1(+/+) DOCA mice compared with Ax1(-/-) DOCA mice. Finally, increased vascular apoptosis in the Ax1(-/-) DOCA mice suggests a likely mechanism for Ax1-dependent effects on hypertension. These data strengthen the pathogenic role for Ax1 in salt-sensitive hypertension. ( Hypertension. 2007; 50: 1057- 1062.).