Rho Kinase Regulates Aortic Vascular Smooth Muscle Cell Stiffness Via Actin/SRF/Myocardin in Hypertension.
Rho Kinase Regulates Aortic Vascular Smooth Muscle Cell Stiffness Via Actin/SRF/Myocardin in Hypertension.
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Rho 激酶在高血压中通过肌动蛋白/SRF/心肌素调节主动脉血管平滑肌细胞僵硬度。
DOI：
10.1159/000485284
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Qiu H
中科院分区：
文献类型：
--
作者：
Zhou N;Lee JJ;Stoll S;Ma B;Costa KD;Qiu H
我们之前的研究表明，内在主动脉平滑肌细胞（VSMC）硬化在衰老和高血压引起的主动脉硬化中起着关键作用。然而，潜在的分子机制仍然很大程度上未知。我们假设 Rho 激酶 (ROCK) 作为一种新型介质，通过血清反应因子 (SRF)/心肌素途径调节内在 VSMC 机械特性，从而调节高血压的主动脉僵硬度和血压。对四个月大的雄性自发性高血压大鼠 (SHR) 和 Wistar-Kyoto (WKY) 大鼠进行了研究。主动脉僵硬度通过超声描记术测量。通过原子力显微镜（AFM）在体外测量 VSMC 的内在机械特性。与 WKY 大鼠相比，SHR 显示主动脉僵硬度和血压显着增加，同时伴随着胸主动脉 (TA) VSMC 显着的细胞硬化和 ROCK 激活。 SHR 中的这些改变被 ROCK 的特异性抑制剂 Y-27632 消除。此外，在 SHR 与 WKY 大鼠的 TA VSMC 中检测到丝状/球状肌动蛋白比率升高，导致 SRF 和心肌素表达及其下游硬度相关基因（包括 α-平滑肌肌动蛋白、SM22、平滑蛋白和肌球蛋白重链 11）上调。相反，SHR TA VSMC 中的这些变化也被抑制 Y-27632。此外，SRF/心肌素的特异性抑制剂 CCG-100602 在 SHR 中的 TA VSMC 硬度体外和体内主动脉壁硬度方面均显示出与 Y-27632 相似的效果。 ROCK 是一种通过 SRF/心肌素信号传导调节主动脉 VSMC 硬度的新型介质，为减少高血压中的主动脉硬化提供了治疗靶点。
Our previous studies demonstrated that intrinsic aortic smooth muscle cell (VSMC) stiffening plays a pivotal role in aortic stiffening in aging and hypertension. However, the underlying molecular mechanisms remain largely unknown. We here hypothesized that Rho kinase (ROCK) acts as a novel mediator that regulates intrinsic VSMC mechanical properties through the serum response factor (SRF)/myocardin pathway and consequently regulates aortic stiffness and blood pressure in hypertension. Four-month old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were studied. Aortic stiffness was measured by echography. Intrinsic mechanical properties of VSMCs were measured by atomic force microscopy (AFM) in vitro. Compared to WKY rats, SHR showed a significant increase in aortic stiffness and blood pressure, which is accompanied by a remarkable cell stiffening and ROCK activation in thoracic aortic (TA) VSMCs. Theses alterations in SHR were abolished by Y-27632, a specific inhibitor of ROCK. Additionally, boosted filamentous/globular actin ratio was detected in TA VSMCs from SHRversus WKY rats, resulting in an up-regulation of SRF and myocardin expression and its downstream stiffness-associated genes including α-smooth muscle actin, SM22, smoothelin and myosin heavy chain 11. Reciprocally, these alterations in SHR TA VSMCs were also suppressed by Y-27632. Furthermore, a specific inhibitor of SRF/myocardin, CCG-100602, showed a similar effect to Y-27632 in SHR in both TA VSMCs stiffness in vitro and aorta wall stiffness in vivo. ROCK is a novel mediator modulating aortic VSMC stiffness through SRF/myocardin signaling which offers a therapeutic target to reduce aortic stiffening in hypertension.
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DOI：
10.1038/nrm2890
发表时间：
2010-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Kureishi, Y;Kobayashi, S;Ito, M
通讯作者：
Ito, M
影响因子：
1.6
作者：
Cecelja M;Chowienczyk P
通讯作者：
Chowienczyk P
DOI：
10.1161/hypertensionaha.114.00921
发表时间：
2014-07
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Mitchell GF
通讯作者：
Mitchell GF
影响因子：
24
作者：
Pu, Jun;Mintz, Gary S.;Maehara, Akiko
通讯作者：
Maehara, Akiko