Phosphodiesterase 3A and Arterial Hypertension
Phosphodiesterase 3A and Arterial Hypertension
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DOI：
10.1161/circulationaha.119.043061
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发表时间：
2020-07-14
期刊：
影响因子：
37.8
通讯作者：
Klussmann, Enno
中科院分区：
文献类型：
--
作者：
Ercu, Maria;Marko, Lajos;Klussmann, Enno
背景：高血压是世界范围内心血管疾病死亡的主要危险因素。常染色体显性遗传性高血压伴短指，临床上类似于耐盐性原发性高血压，在50岁之前死于中风。我们最近发现了编码磷酸二酯酶3A(PDE3A)的基因；然而，缺乏对遗传缺陷的体内模拟，从而显示突变的PDE3A参与其中。方法：采用基因定位、测序、转基因技术、CRISPR-Cas9基因编辑、免疫印迹和荧光共振能量转移等方法。我们发现了新的患者，进行了广泛的动物表型分析，并探索了新的信号通路。结果：我们描述了PDE3A基因15个碱基对(BP)区域内的一种新的突变，并将该片段定义为高血压伴短指畸形的突变热点。这些突变会导致酶活性的增加。一个CRISPR/Cas9产生的大鼠模型，在热点内有一个类似于人的缺失的9个碱基的缺失，重述了高血压伴短趾。在小鼠中，突变的转基因PDE3A在平滑肌细胞中过表达证实了突变的PDE3A会导致高血压。突变的PDE3A酶在其磷酸化过程中表现出一致的变化，并与14-3-3 theta接头蛋白的相互作用增加。这种异常信号与血管平滑肌细胞增殖增加以及血管形态和功能改变有关。结论：突变的PDE3A基因驱动了导致高血压的外周血管阻力增加的机制。我们提出了两个新的动物模型，将有助于进一步阐明潜在的机制。我们的发现可能有助于寻找新的降压治疗方法。
Background: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A (PDE3A); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking. Methods: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. Results: We describe a novel mutation within a 15 base pair (bp) region of thePDE3Agene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3 theta adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. Conclusions: The mutatedPDE3Agene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.