Elucidating PDE3A-caused hypertension and uncovering new treatment targets

• Applicants: Privatdozentin Dr. Sylvia Bähring; Privatdozent Dr. Enno Klußmann
• Subject Area: Pharmacology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324630081

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.

• DFG Programme: Research Grants