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

Item Type:Article
Title:Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly
Creators Name:Toka, O. and Tank, J. and Schächterle, C. and Aydin, A. and Maass, P.G. and Elitok, S. and Bartels-Klein, E. and Hollfinger, I. and Lindschau, C. and Mai, K. and Boschmann, M. and Rahn, G. and Movsesian, M.A. and Müller, T. and Doescher, A. and Gnoth, S. and Mühl, A. and Toka, H.R. and Wefeld-Neuenfeld, Y. and Utz, W. and Töpper, A. and Jordan, J. and Schulz-Menger, J. and Klussmann, E. and Bähring, S. and Luft, F.C.
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.
Keywords:Blood Platelets, Brachydactyly, Cyclic Nucleotide Phosphodiesterases, Type 3, Genetics, HTNB, Hypertension
Publisher:American Heart Association
Page Range:800-808
Date:October 2015
Official Publication:https://doi.org/10.1161/HYPERTENSIONAHA.115.06000
PubMed:View item in PubMed

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