Elucidating PDE3A-caused hypertension and uncovering new treatment targets

阐明 PDE3A 引起的高血压并发现新的治疗靶点

• 批准号: 324630081
• 负责人: Privatdozentin Dr. Sylvia Bähring
• 金额: --
• 依托单位: Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/324630081?language=en
• 关键词: Elucidating; PDE3A; caused; hypertension; uncovering

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.

对孟德尔条件的研究发现了对血压产生巨大影响的新基因。目前所发现的所有机制都涉及远端肾单位的钠转运。我们最近发现磷酸二酯酶-3A（PDE 3A）突变导致50岁以前血压升高50 mm Hg和中风，这是遗传性高血压的第一种非盐形式，常染色体显性高血压伴短指（HTNB）。这些突变增加了蛋白激酶A（PKA）介导的PDE 3A磷酸化，导致功能获得，cAMP水解活性增加，血管平滑肌细胞（VSMC）增殖增强。奇怪的是，我们在患者中没有观察到肥大或心力衰竭，并发现在心肌细胞中，PDE 3A与基于A-激酶锚定蛋白18（AKAP 18）的信号体形成磷酸化依赖性复合物。我们获得了AKAP 18-PKA相互作用的三维结构。现在，我们将确定导致综合征血管表型的PDE 3A突变的分子后果。我们将使用我们的间充质基质干细胞（MSC），我们分化成VSMC。我们将表征突变对细胞内信号传导的影响，特别是对蛋白质-蛋白质相互作用中的畸变的影响，这些畸变改变了限定的细胞（cAMP）隔室中的信号传导。我们将开发用于抑制疾病相关蛋白质-蛋白质相互作用的药理学试剂，用于功能分析。然后，我们将验证这种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，即外周血管阻力增加有新的认识。我们的工作可以建立一个PDE 3A导向的信号通路作为一个药理学目标和基础的新的治疗概念，用于预防和治疗原发性高血压。

项目成果

Local cyclic adenosine monophosphate signalling cascades—Roles and targets in chronic kidney disease

• DOI: 10.1111/apha.13641
• 发表时间: 2021-03
• 期刊: Acta Physiologica
• 影响因子: 6.3
• 作者: Anastasiia Sholokh;E. Klussmann

New aspects in cardiac L-type Ca2+ channel regulation.

• DOI: 10.1042/bst20190229
• 发表时间: 2020-02
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Tamara Pallien;E. Klussmann

Phosphodiesterase 3A and Arterial Hypertension

• DOI: 10.1161/circulationaha.119.043061
• 发表时间: 2020-07-14
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Ercu, Maria;Marko, Lajos;Klussmann, Enno
• 通讯作者: Klussmann, Enno

Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

• DOI: 10.1073/pnas.1822113116
• 发表时间: 2019-07-02
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Omar, Faisa;Findlay, Jane E.;Henderson, David J. P.
• 通讯作者: Henderson, David J. P.

Reconstitution of β-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms

• DOI: 10.1073/pnas.2100021118
• 发表时间: 2021-05-25
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Katz, Moshe;Subramaniam, Suraj;Dascal, Nathan
• 通讯作者: Dascal, Nathan