Abstract 039: The PDE3A Gene Regulates Blood Pressure

Abstract

Hypertension is the greatest driver of cardiovascular disease, the most common cause of death. Finding novel model mechanisms for blood-pressure (BP) regulation is an important goal. Autosomal-dominant hypertension with brachydactyly (HTNB) clinically resembles salt-resistant essential hypertension and causes death by stroke, commonly before age 50 years. We identified mutated phosphodiesterase 3A as responsible earlier; however, definitive mechanistic proof and animal models were lacking. We now describe new kindreds, one substituted within the earlier-described regulatory region (G449S), and another with a mutation causing an amino acid substitution within the PDE3A enzymatic pocket (R864C). Both exhibit the HTNB phenotype. Mutant PDE3A (T445N) overexpression in mouse vascular smooth muscle cells causes hypertension (mean telemetry BP 130/88 mm Hg vs littermate control 115/84 mm Hg, p<0.01). A 9 base-pair, three amino acid (3AA) deletion within the regulatory segment (using CRISPR-Cas9 technology), recapitulates HTNB in the rat, including the skeletal (with micro CT) phenotype. Three-weeks of radiotelemetry in homozygous 3AA+/+ rats at age 6 months revealed mean systolic BP 151, diastolic BP 119 mm Hg; heterozygous 3AA+/- (like the patients) showed 148/105 mm Hg; PDE3A knockout (frame-shift mutation) rats exhibited the lowest pressures at 115/87 mm Hg (all p<0.001) vs. BP of wild-type Sprague-Dawley rats at mean 126/90 mm Hg. R864C causes increased oligomerization. Furthermore, R864C, T445N, and 3AA all cause increased interactions at the scaffolding protein, 14-3-3 theta, compared to the wild-type (P<0.05). With two separate rodent models, our data not only direct mechanistic hypertension research along non-renal pathways, but also identify new areas of possible therapeutic intervention. We suggest that PDE3A could represent a generalizable novel therapeutic target in all instances of elevated blood pressure.