Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension
Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension
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DOI：
10.1152/ajpheart.00654.2011
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发表时间：
2011-11-01
影响因子：
4.8
通讯作者：
Bonnet, Sebastien
中科院分区：
文献类型：
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作者：
Paulin, Roxane;Meloche, Jolyane;Bonnet, Sebastien
Paulin R，Meloche J，Jacob MH，Bisserier M，Courboulin A，Bonnet S.脱氢表雄酮抑制肺动脉高压中Src/STAT 3的组成性激活Am J Physiol Heart Circ Physiol 301：H1798-H1809，2011.首次发表于2011年9月2日; doi：10.1152/ajpheart.00654.2011。肺动脉高压（PAH）是一种以肺动脉平滑肌细胞（PASMC）增殖增强和凋亡抑制为特征的阻塞性血管病变。这种表型通过Src/信号转导子和转录激活子3（STAT 3）轴的激活来维持，通过涉及miR-204的正反馈环来维持，随后是其下游靶标如Pim 1和活化T细胞的核因子（NFATc 2）的异常表达/激活。脱氢表雄酮（DHEA）是一种类固醇激素，可逆转全身血管的血管重塑。由于STAT 3被描述为由DHEA调节，我们假设DHEA通过抑制Src/STAT 3组成性激活来逆转人肺动脉高压。使用从PAH患者（n = 3）中分离的PASMCs，我们证明DHEA降低Src和STAT 3激活（Western印迹和核转位试验），导致Pim 1，NFATc 2表达/激活（定量RT-PCR和Western印迹）以及Survivin和骨形态发生蛋白受体2（BMPR 2）和miR-204的上调显著降低。脱氢表雄酮对Src/STAT 3轴的抑制作用与1）线粒体膜电位相关（四甲基罗丹明甲酯高氯酸盐; n = 150; P < 0.05）去极化使凋亡增加25%（末端脱氧核苷酸转移酶dUTP介导的缺口末端标记; n = 150; P < 0.05）;和2）降低细胞内Ca 2+浓度（fluo-3AM; n = 150; P < 0.05）和增殖30%（PCNA）。最后，在体内类似于STAT 3抑制DHEA改善实验PAH（野百合碱大鼠）通过降低平均PA压力和右心室肥大。这些作用与Src、STAT 3、Pim 1、NFATc 2和Survivin的抑制以及BMPR 2和miR-204的上调相关。我们证明DHEA部分通过抑制Src/STAT 3逆转肺动脉高压。
Paulin R, Meloche J, Jacob MH, Bisserier M, Courboulin A, Bonnet S. Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 301: H1798-H1809, 2011. First published September 2, 2011; doi:10.1152/ajpheart.00654.2011.-Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This phenotype is sustained by the activation of the Src/signal transducer and activator of transcription 3 (STAT3) axis, maintained by a positive feedback loop involving miR-204 and followed by an aberrant expression/activation of its downstream targets such as Pim1 and nuclear factor of activated T-cells (NFATc2). Dehydroepiandrosterone (DHEA) is a steroid hormone shown to reverse vascular remodeling in systemic vessels. Since STAT3 has been described as modulated by DHEA, we hypothesized that DHEA reverses human pulmonary hypertension by inhibiting Src/STAT3 constitutive activation. Using PASMCs isolated from patients with PAH (n = 3), we demonstrated that DHEA decreases both Src and STAT3 activation (Western blot and nuclear translocation assay), resulting in a significant reduction of Pim1, NFATc2 expression/activation (quantitative RT-PCR and Western blot), as well as Survivin and upregulation of bone morphogenetic protein receptor 2 (BMPR2) and miR-204. Src/STAT3 axis inhibition by DHEA is associated with 1) mitochondrial membrane potential (tetramethylrhodamine methyl-ester perchlorate; n = 150; P < 0.05) depolarization increasing apoptosis by 25% (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling; n = 150; P < 0.05); and 2) decreased intracellular Ca2+ concentration (fluo-3 AM; n = 150; P < 0.05) and proliferation by 30% (PCNA). Finally, in vivo similarly to STAT3 inhibition DHEA improves experimental PAH (monocrotaline rats) by decreasing mean PA pressure and right ventricle hypertrophy. These effects were associated with the inhibition of Src, STAT3, Pim1, NFATc2, and Survivin and the upregulation of BMPR2 and miR-204. We demonstrated that DHEA reverses pulmonary hypertension in part by inhibiting the Src/STAT3.