Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (<i>PDE3A</i>)

Kim, You Ran; Yi, Myeongjin; Cho, Sun-Ah; Kim, Woo Young; Min, Ji-Young; Shin, Jae‐Gook; Lee, Su-Jun

doi:10.1111/ahg.12411

Cited by 3 publications

(1 citation statement)

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“…C707R and A980V substitutions at the N and C termini of the PDE3A catalytic domain reduced enzyme activity, 46 indicating that catalytic domain mutants do not generally increase PDE3A activity. Our data suggest increased dimerization/self-assembly of mutant PDE3A as a mechanism underlying the hyperactivity.…”

Section: Discussionmentioning

confidence: 99%

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

et al. 2022

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Research progress in small-molecule modulators of protein-protein interactions

Yang,

2023

Chin. Sci. Bull.

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Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival

Singhal

Al-Marsoummi

Vomhof-DeKrey

et al. 2023

Cancers

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The Schlafen 12 (SLFN12) protein regulates triple-negative breast cancer (TNBC) growth, differentiation, and proliferation. SLFN12 mRNA expression strongly correlates with TNBC patient survival. We sought to explore SLFN12 overexpression effects on in vivo human TNBC tumor xenograft growth and performed RNA-seq on xenografts to investigate related SLFN12 pathways. Stable SLFN12 overexpression reduced tumorigenesis, increased tumor latency, and reduced tumor volume. RNA-seq showed that SLFN12 overexpressing xenografts had higher luminal markers levels, suggesting that TNBC cells switched from an undifferentiated basal phenotype to a more differentiated, less aggressive luminal phenotype. SLFN12-overexpressing xenografts increased less aggressive BC markers, HER2 receptors ERBB2 and EGFR expression, which are not detectable by immunostaining in TNBC. Two cancer progression pathways, the NAD signaling pathway and the superpathway of cholesterol biosynthesis, were downregulated with SLFN12 overexpression. RNA-seq identified gene signatures associated with SLFN12 overexpression. Higher gene signature levels indicated good survival when tested on four independent BC datasets. These signatures behaved differently in African Americans than in Caucasian Americans, indicating a possible biological difference between these races that could contribute to the worse survival observed in African Americans with BC. These results suggest an increased SLFN12 expression modulates TNBC aggressiveness through a gene signature that could offer new treatment targets.

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Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (PDE3A)

Cited by 3 publications

References 40 publications

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage

Research progress in small-molecule modulators of protein-protein interactions

Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival

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