Phosphodiesterase 3A and Arterial Hypertension
| العنوان: | Phosphodiesterase 3A and Arterial Hypertension |
|---|---|
| المؤلفون: | Fatimunnisa Qadri, Russell Hodge, Kerstin Zühlke, Yoland-Marie Anistan, Martin Lehmann, Dmitry Tsvetkov, Lajos Markó, Sara Maghsodi, Astrid Mühl, Michael Russwurm, Atakan Aydin, Rosana Molé Illas, Mihail Todiras, Burkhard Wiesner, Carolin Schächterle, Elena Popova, Maria Ercu, Ilona Kamer, Martin Taube, Enno Klussmann, Jenny Eichhorst, Sofia K. Forslund, Arnd Heuser, Nerine Gregersen, Michael Bader, Stefanie Schelenz, Norbert Hubner, Stephan Walter, Philipp G. Maass, Ralph Plehm, Theda U P Bartolomaeus, Yingqiu Cui, Reika Langanki, Bärbel Pohl, Andrea Geelhaar, Hanna Napieczynska, Sylvia Bähring, Friedrich C. Luft, Dominik N. Müller, Maik Gollasch |
| المصدر: | Circulation. 142:133-149 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Genotype, DNA Mutational Analysis, 030204 cardiovascular system & hematology, Animals, Genetically Modified, Renin-Angiotensin System, Cardiovascular death, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Internal medicine, Animals, Medicine, Arterial Pressure, Genetic Predisposition to Disease, Risk factor, Alleles, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, business.industry, Brachydactyly, Phosphodiesterase, medicine.disease, Immunohistochemistry, Cyclic Nucleotide Phosphodiesterases, Type 3, Pedigree, Rats, Enzyme Activation, Isoenzymes, Radiography, Disease Models, Animal, Phenotype, Blood pressure, Amino Acid Substitution, Gene Targeting, Hypertension, Mutation, Cardiology, CRISPR-Cas Systems, Cardiology and Cardiovascular Medicine, business, Biomarkers |
| الوصف: | Background: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A ( PDE3A ); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking. Methods: We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. Results: We describe a novel mutation within a 15 base pair (bp) region of the PDE3A gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3θ adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function. Conclusions: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments. |
| تدمد: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.119.043061 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5e71b67310d65b69c273c2c9a91af2db https://doi.org/10.1161/circulationaha.119.043061 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5e71b67310d65b69c273c2c9a91af2db |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244539 00097322 |
|---|---|
| DOI: | 10.1161/circulationaha.119.043061 |