Abstract 12025: Phosphodiesterase 3A Mutations Limit Hypertension-Induced Cardiac Damage

Abstract

Hypertension affects more than 1 billion people worldwide and can cause cardiac hypertrophy and ultimately heart failure, a condition with an unmet medical need. We have shown that missense mutations in a 15 bp regulatory domain of the phosphodiesterase 3A ( PDE3A ) gene cause hypertension with brachydactyly type E (HTNB). 1, 2 We recently discovered two HTNB families with new mutations in the region encoding the catalytic domain of PDE3A. CRISPR-Cas9 was used to generate rat models of HTNB by introducing mutations in the regulatory or catalytic domain of the PDE3A gene. Surprisingly, despite the hypertension the hearts of the HTNB rats, even in response to catecholamine challenge, were similar to those of the wild type controls, as indicated by echocardiography. mRNA and protein expression analyses did hardly detect significant differences between the left ventricles of the mutant and wild type animals. However, the mutations consistently caused aberrations of PDE3A phosphorylation, enhanced interaction with the adaptor protein, 14-3-3θ, and aberrant cellular localisation. Fluorescence resonance energy transfer (FRET) experiments showed that all PDE3A mutants were hyperactive. Calcium imaging of cardiac myocytes isolated from the rat models revealed differences in calcium cycling between the mutants and wild type animals. Taken together, the data indicate that mutant PDE3A causes aberrant signalling, and suggest that an enhanced local activity of PDE3A is cardioprotective and may provide a basis for new approaches towards heart failure treatment. 1.Maass PG et al. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet . 2015;47:647-53.2.Ercu M, Marko L et al. Phosphodiesterase 3A and Arterial Hypertension. Circulation . 2020;142:133-149. HTNB Consortium: Ryan Walker-Gray, Anastasiia Sholokh, Claudia Loica, Tamara Pallien, Michael B. Mücke, Kerstin Zühlke, Andrea Geelhaar, Michael Russwurm, Lajos Markó, Theda U.P. Bartolomaeus, Hanna Napieczynska, Stefanie Schelenz, Martin Taube, Arnd Heuser, Tatiana Borodina, Daniele Yumi Sunaga-Franze, Jenny Eichhorst, Martin Lehmann, Fatimunnisa Qadri, Elena Popova, Reika Langanki, Sofia K. Forslund, Dominik N. Müller, Norbert Hübner, Sylvia Båhring, Michael Bader