ID family protein expression and regulation in hypoxic pulmonary hypertension
ID family protein expression and regulation in hypoxic pulmonary hypertension
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DOI：
10.1152/ajpregu.00866.2009
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发表时间：
2010-12-01
影响因子：
2.8
通讯作者：
de Caestecker, Mark P.
中科院分区：
文献类型：
--
作者：
Lowery, Jonathan W.;Frump, Andrea L.;de Caestecker, Mark P.
Lowery JW，Frump AL，Anderson L，DiCarlo GE，Jones MT，De Caestecker议员。ID家族蛋白在缺氧性肺动脉高压中的表达及调控。Am J Physiol Regul Integr Comp Physiol 299：R1463-R1477,2010.2010年9月29日首次出版；DOI：10.1152/ajpregu.00866.2009。-骨形态发生蛋白信号与肺动脉高压(PH)的发展有关。分化抑制蛋白(ID1-4)是一类碱性螺旋-环-螺旋转录因子家族，是BMP信号通路的下游靶标，但ID蛋白在PH发生发展中的作用尚不清楚。为了解决这一问题，我们评估了低氧诱导的PH小鼠模型中肺ID蛋白的表达。缺氧性肺血管平滑肌细胞(VSMCs)在体内存在ID1和ID3的选择性诱导表达，低氧诱导的VSMCs中ID1和ID3的表达呈BMP依赖性增加。ID4蛋白在小鼠肺中几乎检测不到，而ID2在体内缺氧的外周VSMCs中被诱导，而在培养的肺VSMCs中不被缺氧或BMP信号所增加。此外，野生型和Id1缺失型小鼠对慢性缺氧的PH反应是无法区分的。这与ID1基因缺失小鼠肺VSMCs中ID3的代偿性增加有关，但与ID2的表达无关。这些发现表明，ID1在建立正常的肺血管对缺氧的反应中是必不可少的，但提示ID3可能补偿了肺VSMC中ID1表达的丢失。综上所述，这些发现表明ID1和ID3在缺氧性肺VSMC中以BMP依赖的方式表达调节，ID1和ID3可能在调节BMP依赖的VSMC对慢性低氧的反应中发挥协同作用。
Lowery JW, Frump AL, Anderson L, DiCarlo GE, Jones MT, de Caestecker MP. ID family protein expression and regulation in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol 299: R1463-R1477, 2010. First published September 29, 2010; doi:10.1152/ajpregu.00866.2009.-Bone morphogenetic protein (BMP) signaling has been linked to the development of pulmonary hypertension (PH). Inhibitors of differentiation (ID) proteins (ID1-4) are a family of basic helix-loop-helix transcription factors that are downstream targets of the BMP signaling pathway, but the role that ID proteins play in the development of PH is unknown. To address this, we evaluated pulmonary expression of ID proteins in a mouse model of hypoxia-induced PH. There is selective induction of ID1 and ID3 expression in hypoxic pulmonary vascular smooth muscle cells (VSMCs) in vivo, and ID1 and ID3 expression are increased by hypoxia in cultured pulmonary VSMCs in a BMP-dependent fashion. ID4 protein is barely detectable in the mouse lung, and while ID2 is induced in hypoxic peripheral VSMCs in vivo, it is not increased by hypoxia or BMP signaling in cultured pulmonary VSMCs. In addition, the PH response to chronic hypoxia is indistinguishable between wild type and Id1 null mice. This is associated with a compensatory increase in ID3 but not ID2 expression in pulmonary VSMCs of Id1 null mice. These findings indicate that ID1 is dispensable for mounting a normal pulmonary vascular response to hypoxia, but suggest that ID3 may compensate for loss of ID1 expression in pulmonary VSMCs. Taken together, these findings indicate that ID1 and ID3 expression are regulated in a BMP-dependent fashion in hypoxic pulmonary VSMCs, and that ID1 and ID3 may play a cooperative role in regulating BMP-dependent VSMC responses to chronic hypoxia.