Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics of Notch1 heterozygous mice in a high-cholesterol diet model.
Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics of Notch1 heterozygous mice in a high-cholesterol diet model.
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DOI：
10.1371/journal.pone.0238407
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Merryman WD
中科院分区：
文献类型：
--
作者：
Joll JE 2nd;Clark CR;Peters CS;Raddatz MA;Bersi MR;Merryman WD
钙化性主动脉瓣疾病（CAVD）是一种致命的疾病，由于人口老龄化，其患病率正在上升。虽然这种疾病很复杂，但人们对它的了解很少，一个有据可查的瓣膜病驱动因素是5-羟色胺激动。5-羟色胺过度表达，如类癌和药物相关激动，如芬氟拉明的使用，与各种瓣膜疾病有关。因此，本研究的目的是确定5-HT 2B 5-羟色胺受体（基因：Htr 2b）的基因消融或药物拮抗是否可以改善钙化性主动脉瓣疾病的血流动力学和组织学进展。将Htr 2b突变小鼠与Notch 1 +/-小鼠（一种已建立的CAVD小动物模型）杂交，以确定基因消融是否影响CAVD进展。为了评估药理学抑制对CAVD进展的影响，用5-HT 2B受体拮抗剂SB 204741处理Notch 1 +/-小鼠。使用超声心动图、组织学、免疫荧光和实时定量聚合酶链反应对小鼠进行分析。htr 2b突变小鼠表现出较低的主动脉瓣峰值速度和平均压力梯度主动脉瓣狭窄的经典血流动力学指标没有并发的左心室改变。然而，5-HT 2B受体拮抗剂不影响血流动力学进展。在任何组中，瓣叶厚度、胶原密度和CAVD相关转录标记物均无显著差异。这项研究表明，Htr 2b的基因消融减弱了Notch 1 +/-小鼠中CAVD的血流动力学发展，但药理学拮抗作用可能需要高剂量或长期治疗来减缓进展。
Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2B serotonin receptor (gene: Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1+/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1+/- mice were treated with the 5-HT2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient–classical hemodynamic indicators of aortic valve stenosis–without concurrent left ventricle change. 5-HT2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1+/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.
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