Reduced mRNA Expression of RGS2 (Regulator of G Protein Signaling-2) in the Placenta Is Associated With Human Preeclampsia and Sufficient to Cause Features of the Disorder in Mice
Reduced mRNA Expression of RGS2 (Regulator of G Protein Signaling-2) in the Placenta Is Associated With Human Preeclampsia and Sufficient to Cause Features of the Disorder in Mice
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DOI：
10.1161/hypertensionaha.119.14056
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发表时间：
2020-02-01
期刊：
影响因子：
8.3
通讯作者：
Grobe, Justin L.
中科院分区：
文献类型：
--
作者：
Perschbacher, Katherine J.;Deng, Guorui;Grobe, Justin L.
G蛋白信号传导的级联特异性终止由RGS（G蛋白信号传导调节剂）家族成员催化，包括RGS 2。血管紧张素、血管加压素和内皮素与先兆子痫有关，已知RGS 2抑制由这些激素激活的G蛋白级联反应。RGS 2突变与人类高血压和先兆子痫及其后遗症风险增加相关。已知RGS家族成员影响母体血管功能，但RGS 2在胎盘内的作用尚未探索。在此，我们假设胎盘内RGS 2表达减少是先兆子痫发生的危险因素。尽管与临床匹配的对照相比，cAMP/CREB信号在受先兆子痫影响的人类妊娠的胎盘中富集，并且已知RGS 2是CREB应答基因，但在受先兆子痫影响的妊娠的胎盘中RGS 2 mRNA减少。实验性降低胎儿胎盘单位内的Rgs 2表达足以在妊娠野生型C57 BL/6 J小鼠中诱导先兆子痫样表型。发现通过cAMP/CREB信号传导对永生化人HTR 8/SVneo滋养层内RGS 2转录的刺激依赖于组蛋白脱乙酰酶活性的活性，更具体地，HDAC 9（组蛋白脱乙酰酶-9）的活性，并且HDAC 9表达在来自受先兆子痫影响的人妊娠的胎盘中减少。我们的结论是胎盘内RGS 2表达减少可能是先兆子痫的机制。更一般地说，这项工作确定RGS 2作为HDAC 9依赖性CREB反应基因，这可能有助于降低RGS 2在先兆子痫胎盘中的表达。
Cascade-specific termination of G protein signaling is catalyzed by the RGS (regulator of G protein signaling) family members, including RGS2. Angiotensin, vasopressin, and endothelin are implicated in preeclampsia, and RGS2 is known to inhibit G protein cascades activated by these hormones. Mutations in RGS2 are associated with human hypertension and increased risk of developing preeclampsia and its sequelae. RGS family members are known to influence maternal vascular function, but the role of RGS2 within the placenta has not been explored. Here, we hypothesized that reduced expression of RGS2 within the placenta represents a risk factor for the development of preeclampsia. Although cAMP/CREB signaling was enriched in placentas from human pregnancies affected by preeclampsia compared with clinically matched controls and RGS2 is known to be a CREB-responsive gene, RGS2 mRNA was reduced in placentas from pregnancies affected by preeclampsia. Experimentally reducing Rgs2 expression within the feto-placental unit was sufficient to induce preeclampsia-like phenotypes in pregnant wild-type C57BL/6J mice. Stimulation of RGS2 transcription within immortalized human HTR8/SVneo trophoblasts by cAMP/CREB signaling was discovered to be dependent on the activity of histone deacetylase activity, and more specifically, HDAC9 (histone deacetylase-9), and HDAC9 expression was reduced in placentas from human pregnancies affected by preeclampsia. We conclude that reduced expression of RGS2 within the placenta may mechanistically contribute to preeclampsia. More generally, this work identifies RGS2 as an HDAC9-dependent CREB-responsive gene, which may contribute to reduced RGS2 expression in placenta during preeclampsia.