Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

Abstract

Background: Phosphodiesterase 3A ( PDE3A ) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective. Methods: We studied new patients. CRISPR-Cas9–engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca 2+ imaging. We used Förster resonance energy transfer and biochemical assays. Results: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme’s catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The β-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca 2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. Conclusions: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.

Cardiac gene therapy with PDE2A limits remodeling and arrhythmias in mouse models of heart failure induced by catecholamines

“…Interestingly, activating mutations in another PDE, PDE3, responsible for a rare disease characterized by the combination of brachydactyly and hypertension, confers cardioprotection despite the increase in afterload. 41 This latter observation supports our initial postulate and our observations reported here and earlier, 17 that increasing rather than decreasing the activity of PDEs in cardiac tissue is beneficial. However, it remains to be demonstrated which PDE will be the most effective to achieve this goal.…”

Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy

“…Our observation that the PDE3A2/SMAD4/HDAC-1 nanodomain also operates in human cardiac myocytes differentiated from 4 independent pluripotent stem cell lines indicates that this pathway may contribute to the negative long-term clinical outcome observed in patients with HF receiving PDE3 inhibitors. In support of the relevance of the nuclear PDE3A2/SMAD4/HDAC-1 nanodomain in vivo, a recent characterization of the PDE3A functional deletion rat model 10 shows that, upon chronic β-AR challenge, the same degree of cardiac remodeling is observed in knockout and in WT rats, despite the knockout animals displaying significantly lower blood pressure ( Figure S15 ), 59 indicating that, in vivo, loss of PDE3A sensitizes the animals to cardiac stress.…”

Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension

“…PDE3A is targeted by several existing drugs, including Cilostazol (peripheral vascular disease), Levosimendan for intravenous therapy for acutely decompensated heart failure and Enoximone (pulmonary hypertension). There are no data currently indicating the use of PDE3A inhibitors for hypertension, however a recent study suggests activation of PDE3A in the heart may protect it from hypertrophy and failure 56 . MAP2K1 ( MEK1 ) is a target of anti-neoplastic agents ( MAP2K1 is altered in 1% of lung and head and neck squamous cell carcinomas) 57,58 .The MAPK pathway is well recognised in BP control and p38-MAPK inhibition has been considered previously as a therapeutic target (which MAP2K activates).…”