DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy.
DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy.
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DOI：
10.1152/ajpheart.00115.2021
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发表时间：
2021-08-01
期刊：
影响因子：
--
通讯作者：
McKinsey TA
中科院分区：
文献类型：
--
作者：
Ferguson BS;Wennersten SA;Demos-Davies KM;Rubino M;Robinson EL;Cavasin MA;Stratton MS;Kidger AM;Hu T;Keyse SM;McKnight RA;Lane RH;Nozik ES;Weiser-Evans MCM;McKinsey TA
肺动脉高压（PH）与肺动脉（PA）的结构重塑有关，因为成纤维细胞、内皮细胞和平滑肌细胞（SMC）过度增殖。肽激素血管紧张素II（ANG II）有助于肺血管重塑，部分是通过其触发细胞外信号调节激酶（ERK 1/2）激活的能力。在这里，我们证明了ERK 1/2磷酸酶，双特异性磷酸酶5（DUSP5），作为ANG II介导的SMC增殖和PH的负调节器的功能。与野生型对照相比，DUSP5 null小鼠输注ANG II开发PH和右心室（RV）肥大。Dusp5基因敲除小鼠的PH与小PA的中层增厚相关，表明DUSP5作为ANG II依赖性SMC增殖的负调节剂在体内发挥作用。与此一致，DUSP5的过表达阻断了ANG II介导的培养的人肺动脉SMC（hPASMCs）的增殖，所述人肺动脉SMC来源于患有特发性PH的患者或失败的供体对照。总的来说，这些数据支持DUSP5作为ANG II介导的ERK信号传导和PASMC增殖的反馈抑制剂的作用，并表明该回路的中断导致不利的心肺重塑。双特异性磷酸酶（DUSPs）在丝裂原活化蛋白激酶的调节中起着关键作用，但它们在心血管系统中的功能仍不清楚。在这里，我们提供的证据表明，DUSP5，它驻留在细胞核和特异性去磷酸化细胞外信号调节激酶（ERK 1/2），阻止肺血管平滑肌细胞增殖。响应于血管紧张素II输注，缺乏DUSP5的小鼠发展肺动脉高压和右心室心肌肥大。这些发现说明DUSP5介导的肺中ERK信号传导的抑制是一种保护机制。
Pulmonary hypertension (PH) is associated with structural remodeling of pulmonary arteries (PAs) because of excessive proliferation of fibroblasts, endothelial cells, and smooth muscle cells (SMCs). The peptide hormone angiotensin II (ANG II) contributes to pulmonary vascular remodeling, in part, through its ability to trigger extracellular signal-regulated kinase (ERK1/2) activation. Here, we demonstrate that the ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5), functions as a negative regulator of ANG II-mediated SMC proliferation and PH. In contrast to wild-type controls, Dusp5 null mice infused with ANG II developed PH and right ventricular (RV) hypertrophy. PH in Dusp5 null mice was associated with thickening of the medial layer of small PAs, suggesting an in vivo role for DUSP5 as a negative regulator of ANG II-dependent SMC proliferation. Consistent with this, overexpression of DUSP5 blocked ANG II-mediated proliferation of cultured human pulmonary artery SMCs (hPASMCs) derived from patients with idiopathic PH or from failed donor controls. Collectively, the data support a role for DUSP5 as a feedback inhibitor of ANG II-mediated ERK signaling and PASMC proliferation and suggest that disruption of this circuit leads to adverse cardiopulmonary remodeling. NEW & NOTEWORTHY Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.
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影响因子：
64.8
作者：
NG, KKF;VANE, JR
通讯作者：
VANE, JR
影响因子：
3.3
作者：
Wickramasekera, Nadi T.;Gebremedhin, Debebe;Harder, David R.
通讯作者：
Harder, David R.
影响因子：
4
作者：
Dickinson, Robin J.;Keyse, Stephen M.
通讯作者：
Keyse, Stephen M.
影响因子：
3.6
作者：
Chen, Lauren L.;Zmuda, Erik J.;Trittmann, Jennifer K.
通讯作者：
Trittmann, Jennifer K.
DOI：
10.1183/09031936.00046612
发表时间：
2012-12
期刊：
The European respiratory journal
影响因子：
--
作者：
Voelkel NF;Gomez-Arroyo J;Abbate A;Bogaard HJ;Nicolls MR
通讯作者：
Nicolls MR