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| Item Type: | Article |
|---|---|
| Title: | Phosphodiesterase 3A and arterial hypertension |
| Creators Name: | Ercu, M., Markó, L., Schächterle, C., Tsvetkov, D., Cui, Y., Maghsodi, S., Bartolomaeus, T.U.P., Maass, P.G., Zühlke, K., Gregersen, N., Hübner, N., Hodge, R., Mühl, A., Pohl, B., Molé-Illas, R., Geelhaar, A., Walter, S., Napieczynska, H., Schelenz, S., Taube, M., Heuser, A., Anistan, Y.M., Qadri, F., Todiras, M., Plehm, R., Popova, E., Langanki, R., Eichhorst, J., Lehmann, M., Wiesner, B., Russwurm, M., Forslund, S.K., Kamer, I., Müller, D.N., Gollasch, M., Aydin, A., Bähring, S., Bader, M., Luft, F.C. and Klussmann, E. |
| Abstract: | BACKGROUND: High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal-dominant hypertension with brachydactyly (HTNB) clinically resembles salt-resistant essential hypertension and causes death by stroke before age 50 years. Recently, we 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 (FRET). We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways. RESULTS: We describe a novel mutation within a 15 bp region of the PDE3A gene and define this segment as mutational hotspot in HTNB. 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 HTNB. 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 two new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments. |
| Keywords: | Hypertension, Genetics, Blood Pressure Regulation, Phosphodiesterase, Animals, Rats |
| Source: | Circulation |
| ISSN: | 0009-7322 |
| Publisher: | American Heart Association |
| Volume: | 142 |
| Number: | 2 |
| Page Range: | 133-149 |
| Date: | 14 July 2020 |
| Additional Information: | Copyright © 2020 American Heart Association, Inc. |
| Official Publication: | https://doi.org/10.1161/CIRCULATIONAHA.119.043061 |
| PubMed: | View item in PubMed |
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