Elucidating PDE3A-caused hypertension and uncovering new treatment targets

孟德尔条件的研究发现了对血压有很大影响的新基因。目前发现的所有机制都涉及远端肾元的钠转运。我们最近发现磷酸二酯酶3a （PDE3A）突变可导致50岁前血压和中风升高50毫米汞柱，这是遗传性高血压的第一种非盐性形式，常染色体显性高血压伴短指畸形（HTNB）。突变增加了蛋白激酶A （PKA）介导的PDE3A磷酸化，导致功能增强，camp水解活性增加，血管平滑肌细胞（VSMC）增殖增强。奇怪的是，我们在我们的患者中没有观察到肥厚或心力衰竭，并发现在心肌细胞中PDE3A与基于a激酶锚定蛋白18 （AKAP18）的信号体形成磷酸化依赖性复合物。我们获得了AKAP18-PKA相互作用的三维结构。现在，我们将定义导致该综合征血管表型的PDE3A突变的分子后果。我们将使用我们的间充质间质干细胞（MSC），我们将其分化为VSMC。我们将描述突变对细胞内信号传导的影响，特别是改变定义细胞（cAMP）区室信号传导的蛋白质-蛋白质相互作用的畸变。我们将开发药物来抑制疾病相关蛋白-蛋白相互作用的功能分析。然后，我们将验证这些相互作用作为与高血压相关的潜在药物靶点。我们期望对高血压的发展，即外周血管阻力的增加，有新的认识。我们的工作可以建立一个以pde3a为导向的信号通路，作为预防和治疗原发性高血压的药理靶点和新治疗理念的基础。

Studies of Mendelian conditions identified new genes that exert large effects on blood pressure. All of the mechanisms identified so far involve sodium transport in the distal nephron. We recently discovered phosphodiesterase-3A (PDE3A) mutations causing a 50 mm Hg increase in blood pressure and stroke before age 50 years, as the first non-salt form of genetic hypertension, autosomal-dominant hypertension with brachydactyly (HTNB). The mutations increased protein kinase A (PKA)-mediated phosphorylation of PDE3A and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced proliferation of vascular smooth muscle cells (VSMC). Oddly, we observed no hypertrophy or heart failure in our patients and found that in cardiac myocytes PDE3A forms a phosphorylation-dependent complex with a signalosome based on the A-kinase anchoring protein 18 (AKAP18). We obtained a 3D structure of the AKAP18-PKA interaction. Now, we will define the molecular consequences of the PDE3A mutations leading to the syndrome's vascular phenotype. We will use our mesenchymal stromal stem cells (MSC), which we differentiated into VSMC. We will characterize the influence of the mutations on intracellular signaling, particularly on aberrations in protein-protein interactions that alter signaling in defined cellular (cAMP) compartments. We will develop pharmacological agents for inhibition of disease-associated protein-protein interactions for functional analyses. We will then validate such interactions as potential drug targets relevant to hypertension. We expect to gain new insight into the development of hypertension, namely the increased peripheral vascular resistance. Our work could establish a PDE3A-directed signaling pathway as a pharmacological target and basis for novel therapeutic concepts for the prevention and treatment of essential hypertension.