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Phosphodiesterase 3A and Arterial Hypertension
Maria Ercu1,2, Lajos Markó2,3,4, Carolin Schächterle1,2,4
1Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany (M.E., C.S., S.M., K.Z., N.H., R.H., A.M., B.P., A.G., H.N., S.S., M. Taube, A.H., F.Q., M. Todiras, R.P., E.P., R.L., S.K.F., D.N.M., A.A., M.B., F.C.L., E.K.).
Insights
A novel mutation in the PDE3A gene causes hypertension with brachydactyly. This discovery provides new animal models and potential targets for developing antihypertensive treatments.
Area of Science:
- Cardiovascular Research
- Genetics
- Molecular Biology
Background:
- High blood pressure (hypertension) is a leading global cause of cardiovascular death.
- Autosomal dominant hypertension with brachydactyly is a severe form of hypertension linked to premature death from stroke.
- Previous research implicated the phosphodiesterase 3A (PDE3A) gene, but in vivo evidence was lacking.
Purpose of the Study:
- To investigate the genetic basis of hypertension with brachydactyly.
- To create and analyze in vivo models of the identified genetic defect.
- To explore the molecular mechanisms underlying PDE3A-associated hypertension.
Main Methods:
- Genetic mapping and sequencing to identify mutations.
- CRISPR-Cas9 gene editing to create animal models (rats and mice).
- Transgenic technology, immunoblotting, and protein interaction studies to analyze PDE3A function.
Main Results:
- A novel mutation hotspot in the PDE3A gene was identified in patients with hypertension with brachydactyly.
- CRISPR-Cas9 generated rat and transgenic mouse models recapitulated the human condition.
- Mutant PDE3A showed increased activity, altered phosphorylation, and enhanced interaction with 14-3-3θ, leading to vascular smooth muscle cell proliferation and altered vessel function.
Conclusions:
- Mutations in the PDE3A gene directly cause hypertension by increasing peripheral vascular resistance.
- The developed animal models offer valuable tools for further research into hypertension mechanisms.
- These findings may pave the way for novel antihypertensive therapies targeting PDE3A signaling.
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.
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