Hypertension 2015-10-01

Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

Okan Toka, Jens Tank, Carolin Schächterle, Atakan Aydin, Philipp G Maass, Saban Elitok, Eireen Bartels-Klein, Irene Hollfinger, Carsten Lindschau, Knut Mai, Michael Boschmann, Gabriele Rahn, Matthew A Movsesian, Thomas Müller, Andrea Doescher, Simone Gnoth, Astrid Mühl, Hakan R Toka, Yvette Wefeld-Neuenfeld, Wolfgang Utz, Agnieszka Töpper, Jens Jordan, Jeanette Schulz-Menger, Enno Klussmann, Sylvia Bähring, Friedrich C Luft

Index: Hypertension 66 , 800-8, (2015)

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Abstract

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population. © 2015 American Heart Association, Inc.