Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension.
Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension.
复制标题
SRF/心肌素的抑制通过针对高血压中的血管平滑肌细胞僵硬来降低主动脉僵硬度。
DOI：
10.1093/cvr/cvw222
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发表时间：
2017-02
影响因子：
10.8
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;Wiener R;Wang C;Costa KD;Qiu H
主动脉僵硬度增加是高血压的基本表现。然而，所涉及的分子机制在很大程度上仍然未知。我们检验了这样一个假设，即在大动脉中，而不是在远端动脉中，异常的固有血管平滑肌细胞（VSMC）的机械特性有助于高血压主动脉硬化的发病机制，由血清反应因子（SRF）/心肌蛋白信号通路介导。本实验观察了4月龄雄性自发性高血压大鼠（SHR）和正常血压WKY大鼠。原子力显微镜下观察到SHR大的传导主动脉与远端主动脉相比有明显的VSMC硬化（P < 0.001），而WKY大鼠无此区域性变化（P > 0.4）。与WKY大鼠相比，SHR大鼠胸主动脉VSMC硬度的增加伴随着SRF表达的9.8倍和myocardin表达的10.5倍的平行增加，导致下游硬度相关基因的显著增加（所有，P < 0.01 vs. WKY）。抑制SRF/myocardin的表达选择性地减弱主动脉VSMC的硬化，并正常化的VSMC的下游目标从SHR，但不是从WKY大鼠分离。在体内，通过皮下渗透微型泵输送的SRF/心肌蛋白抑制剂治疗2周显著降低了SHR的主动脉僵硬度，然后降低了血压，但在WKY大鼠中没有，尽管在此时间范围内未检测到主动脉壁重塑的伴随变化。SRF/myocardin信号通路是影响主动脉VSMC力学特性的重要介质，在高血压病的病理性主动脉硬化中起重要作用。通过药理学抑制SRF/myocardin信号传导来减弱主动脉VSMC硬化，这为通过靶向导致主动脉硬化的细胞来治疗高血压提供了一种新的治疗策略。
Increased aortic stiffness is a fundamental manifestation of hypertension. However, the molecular mechanisms involved remain largely unknown. We tested the hypothesis that abnormal intrinsic vascular smooth muscle cell (VSMC) mechanical properties in large arteries, but not in distal arteries, contribute to the pathogenesis of aortic stiffening in hypertension, mediated by the serum response factor (SRF)/myocardin signalling pathway. Four month old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Using atomic force microscopy, significant VSMC stiffening was observed in the large conducting aorta compared with the distal arteries in SHR (P < 0.001), however, this regional variation was not observed in WKY rats (P > 0.4). The increase of VSMC stiffness was accompanied by a parallel increase in the expression of SRF by 9.8-fold and of myocardin by 10.5-fold in thoracic aortic VSMCs from SHR vs. WKY rats, resulting in a significant increase of downstream stiffness-associated genes (all, P < 0.01 vs. WKY). Inhibition of SRF/myocardin expression selectively attenuated aortic VSMC stiffening, and normalized downstream targets in VSMCs isolated from SHR but not from WKY rats. In vivo, 2 weeks of treatment with SRF/myocardin inhibitor delivered by subcutaneous osmotic minipump significantly reduced aortic stiffness and then blood pressure in SHR but not in WKY rats, although concomitant changes in aortic wall remodelling were not detected during this time frame. SRF/myocardin pathway acts as a pivotal mediator of aortic VSMC mechanical properties and plays a central role in the pathological aortic stiffening in hypertension. Attenuation of aortic VSMC stiffening by pharmacological inhibition of SRF/myocardin signalling presents a novel therapeutic strategy for the treatment of hypertension by targeting the cellular contributors to aortic stiffness.