Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2
Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2
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DOI：
10.1152/ajplung.00173.2017
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发表时间：
2017-09-01
影响因子：
4.9
通讯作者：
Fredenburgh, Laura E.
中科院分区：
文献类型：
--
作者：
Dieffenbach, Paul B.;Haeger, Christina Mallarino;Fredenburgh, Laura E.
肺动脉僵硬度是肺动脉高压（PH）死亡率的独立危险因素，在PH病理生理学中起着关键作用。我们的实验室最近已经证明了在实验PH中早期的动脉硬化，沿着有机械生物学反馈回路的证据，动脉硬化通过该反馈回路促进进一步的细胞重塑行为（Liu F，Haeger CM，Dieffenbach PB，Sicard D，Chrobak I，Coronata AM，苏亚雷斯Velandia MM，Vitali S，Colas RA，Norris PC，Marinkovic A，Liu X，Ma J，Rose CD，Lee SJ，Comhair SA，Erzurum SC，McDonald JD，Serhan CN，沃尔什SR，Tschumperlin DJ，Freden-burgh LE. JCI Insight 1：e86987，2016）。环氧合酶-2（考克斯-2）和前列腺素信号传导与僵硬度介导的调节有关，前列腺素活性与体外基质僵硬度和重塑行为以及啮齿动物PH模型中的疾病进展呈负相关。机械信号传导转化为肺血管细胞中考克斯-2活性降低的机制尚不清楚。本工作研究了转录调节因子Yes相关蛋白（雅普）和含WW结构域的转录调节因子1（WWTR 1，a.k.a.，TAZ），其是下游机械信号传导的已知驱动器，在介导肺动脉平滑肌细胞（PASMC）中考克斯-2和前列腺素活性的刚性诱导的变化中。我们发现雅普/TAZ活性在PAH PASMCs和实验性PH中增加，并且对于刚度依赖性重塑表型的发展是必要的。敲低雅普和TAZ显著诱导COX-2表达和下游前列腺素产生约3倍，而过表达雅普或TAZ将考克斯-2表达和前列腺素产生降低至接近不可检测的水平。总之，我们的研究结果证明了一个刚度依赖性雅普/TAZ介导的正反馈回路，通过降低考克斯-2和前列腺素活性来驱动PASMCs的重塑表型。通过操纵雅普/TAZ信号传导中断这种关键的机械生物学反馈回路并增强局部前列腺素活性的能力为PH的治疗提供了一种非常有吸引力的新策略。
Pulmonary arterial stiffness is an independent risk factor for mortality in pulmonary hypertension (PH) and plays a critical role in PH pathophysiology. Our laboratory has recently demonstrated arterial stiffening early in experimental PH, along with evidence for a mechanobiological feedback loop by which arterial stiffening promotes further cellular remodeling behaviors (Liu F, Haeger CM, Dieffenbach PB, Sicard D, Chrobak I, Coronata AM, Suarez Velandia MM, Vitali S, Colas RA, Norris PC, Marinkovic A, Liu X, Ma J, Rose CD, Lee SJ, Comhair SA, Erzurum SC, McDonald JD, Serhan CN, Walsh SR, Tschumperlin DJ, Freden-burgh LE. JCI Insight 1: e86987, 2016). Cyclooxygenase-2 (COX-2) and prostaglandin signaling have been implicated in stiffness-mediated regulation, with prostaglandin activity inversely correlated to matrix stiffness and remodeling behaviors in vitro, as well as to disease progression in rodent PH models. The mechanism by which mechanical signaling translates to reduced COX-2 activity in pulmonary vascular cells is unknown. The present work investigated the transcriptional regulators Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (WWTR1, a.k.a., TAZ), which are known drivers of downstream mechanical signaling, in mediating stiffness-induced changes in COX-2 and prostaglandin activity in pulmonary artery smooth muscle cells (PASMCs). We found that YAP/TAZ activity is increased in PAH PASMCs and experimental PH and is necessary for the development of stiffness-dependent remodeling phenotypes. Knockdown of YAP and TAZ markedly induces COX-2 expression and downstream prostaglandin production by approximately threefold, whereas overexpression of YAP or TAZ reduces COX-2 expression and prostaglandin production to near undetectable levels. Together, our findings demonstrate a stiffness-dependent YAP/TAZ-mediated positive feedback loop that drives remodeling phenotypes in PASMCs via reduced COX-2 and prostaglandin activity. The ability to interrupt this critical mechanobiological feedback loop and enhance local prostaglandin activity via manipulation of YAP/TAZ signaling presents a highly attractive novel strategy for the treatment of PH.