Vascular smooth muscle Jak2 mediates angiotensin II-induced hypertension via increased levels of reactive oxygen species
Vascular smooth muscle Jak2 mediates angiotensin II-induced hypertension via increased levels of reactive oxygen species
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DOI：
10.1093/cvr/cvr059
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发表时间：
2011-07-01
影响因子：
10.8
通讯作者：
Sayeski, Peter P.
中科院分区：
文献类型：
--
作者：
Kirabo, Annet;Kearns, Patrick N.;Sayeski, Peter P.
目的研究血管平滑肌细胞（VSMC）上表达的血管紧张素Ⅱ（Ang Ⅱ）AT（1）受体与Jak 2信号通路的偶联。然而，这种组织特异性偶联的重要性知之甚少。本研究的目的是确定VSMC来源的Jak 2在血管紧张素II介导的高血压中的重要性。方法和结果使用Cre-loXP系统有条件地消除小鼠平滑肌细胞内Jak 2酪氨酸激酶的表达。慢性血管紧张素II输注后，平均动脉压（MAP）的增加显着衰减时，与同窝对照组相比，在Jak 2基因敲除小鼠。VSMC Jak 2基因敲除小鼠也可免受Ang II诱导的血管重塑。VSMC Jak 2基因敲除小鼠的主动脉环通过增加一氧化氮（NO）的生物利用度，表现出Ang II诱导的收缩减少和内皮依赖性舒张增强。与对照组相比，VSMC Jak 2空表达组细胞内过氧化氢水平、Rho激酶活性和细胞内Ca（2+）水平均较对照组低。结论VSMC Jak 2表达与活性氧（ROS）增加有关。因此，VSMC衍生的Jak 2酪氨酸激酶通过多种非冗余机制调节整体血管张力。
Aims Angiotensin II (Ang II) type AT(1) receptors expressed on vascular smooth muscle cells (VSMCs) couple to the Jak2 signalling pathway. However, the importance of this tissue-specific coupling is poorly understood. The purpose of this investigation was to determine the importance of VSMC-derived Jak2 in angiotensin II-mediated hypertension.Methods and results The Cre-loxP system was used to conditionally eliminate Jak2 tyrosine kinase expression within the smooth muscle cells of mice. Following chronic Ang II infusion, the resulting increase in mean arterial pressure (MAP) was significantly attenuated in the Jak2 null mice when compared with littermate controls. The VSMC Jak2 null mice were also protected from the Ang II-induced vascular remodelling. Aortic rings from the VSMC Jak2 null mice exhibited reduced Ang II-induced contraction and enhanced endothelial-dependent relaxation via increased nitric oxide (NO) bioavailability. When compared with controls, the VSMC Jak2 nulls also had lower levels of hydrogen peroxide, Rho kinase activity, and intracellular Ca(2+) in response to Ang II.Conclusions The data indicate that VSMC Jak2 expression is involved in the pathogenesis of Ang II-dependent hypertension due to the increased presence of reactive oxygen species (ROS). As such, VSMC-derived Jak2 tyrosine kinase modulates overall vascular tone via multiple, non-redundant mechanisms.