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Paper of the Month

June 2020

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Phosphodiesterase 3A and arterial hypertension. Circulation (2020) DZHK authors: M. Ercu*, L. Markó*, C. Schächterle, D. Tsvetkov, T. U. P. Bartolomaeus, N. Hübner, S. K. Forslund, D. N. Müller, M. Gollasch, M. Bader, Friedrich C. Luft** and E. Klussmann**

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More than a billion people worldwide are hypertensive and about eight million die annually directly because of hypertension. Autosomal-dominant hypertension with brachydactyly (HTNB) is clinically similar to essential hypertension. The systolic blood pressures of HTNB patients ranges from 170-250 mmHg and their diastolic blood pressures from 100-150 mmHg. If untreated, the patients die of stroke before aged 50 years. Several authors of the new study had previously identified seven unrelated families worldwide with mutations in the gene encoding phosphodiesterase (PDE)3A. The mutations resulted in increased enzyme activity; however, no animal models of the genetic defect were available showing an involvement of the PDE3A mutations and to provide treatment utility.

The scientists have now identified a further mutation in the PDE3A gene in a family with HTNB that pinpoints all HTNB mutations in the gene to a 15 bp hotspot region. A CRISPR/Cas9-engineered rat model with a 9 bp deletion in this region fully recapitulated all the human HTNB phenotypes. Overexpression of mutant PDE3A in vascular smooth muscle cells of mice also caused severe hypertension.
PDE3A hydrolyses the second messenger cAMP and thereby terminates cAMP signaling. Mutant PDE3A is indeed hyperactive and engages in protein-protein interactions that are different from those of the wildtype enzyme. Higher PDE3A activity could rewire cellular signaling in vascular smooth muscle cells. Further analyses revealed that in the animals the hypertension is not caused by aberrations of the renin-angiotensin-aldosterone system or the heart, as in humans.

This study provides valuable insight into molecular mechanisms underlying hypertension because it directly focusses attention on peripheral vascular resistance. The new animal models could lead to new approaches for antihypertensive treatments.

*contributed equally, **co-correspondent