ArticleJournal of the American College of Cardiology2019
A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium.
Article in Journal of the American College of Cardiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 22 citations in OpenAlex.
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- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- Regulation of Hsa-miR-4639-5p expression and its potential role in the pathogenesis of Parkinson's disease.Aging cell · 2023Article
- Levosimendan increases the phosphorylation state of phospholamban in the isolated human atrium.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
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- A Mutation in Endogenous saRNA miR-23a Influences Granulosa Cells Response to Oxidative Stress.Antioxidants (Basel, Switzerland) · 2022Article
- Medical Therapies for Heart Failure in Hypoplastic Left Heart Syndrome.Journal of cardiovascular development and disease · 2022Article
- Role of lncSLCO1C1 in gastric cancer progression and resistance to oxaliplatin therapy.Clinical and translational medicine · 2022Article
- Potassium Alginate Oligosaccharides Alter Gut Microbiota, and Have Potential to Prevent the Development of Hypertension and Heart Failure in Spontaneously Hypertensive Rats.International journal of molecular sciences · 2021Article
- Circulating cyclic adenosine monophosphate concentrations in milrinone treated paediatric patients after congenital heart surgery.Cardiology in the young · 2021Observational
- Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (PDE3A).Annals of human genetics · 2021Article
- Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure.Cardiovascular drugs and therapy · 2020Review
- Heart failure in single right ventricle congenital heart disease: physiological and molecular considerations.American journal of physiology. Heart and circulatory physiology · 2020Review
- To Explore the Mechanism and Equivalent Molecular Group of Fuxin Mixture in Treating Heart Failure Based on Network Pharmacology.Evidence-based complementary and alternative medicine : eCAM · 2020Article
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15 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundThe phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit.
objectivesThe authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF.
methodsPDE3A promoter studies were performed in a cloned luciferase construct. In human left ventricular (LV) preparations, mRNA expression was measured by reverse transcription polymerase chain reaction, and PDE3 enzyme activity by cAMP-hydrolysis.
resultsThe authors identified a 29-nucleotide (nt) insertion (INS)/deletion (DEL) polymorphism in the human PDE3A gene promoter beginning 2,214 nt upstream from the PDE3A1 translation start site. Transcription factor ATF3 binds to the INS and represses cAMP-dependent promoter activity. In explanted failing LVs that were homozygous for PDE3A DEL and had been treated with PDE3i pre-cardiac transplantation, PDE3A1 mRNA abundance and microsomal PDE3 enzyme activity were increased by 1.7-fold to 1.8-fold (p < 0.05) compared with DEL homozygotes not receiving PDE3i. The basis for the selective up-regulation in PDE3A gene expression in DEL homozygotes treated with PDE3i was a cAMP response element enhancer 61 nt downstream from the INS, which was repressed by INS. The DEL homozygous genotype frequency was also enriched in patients with HF.
conclusionsA 29-nt INS/DEL polymorphism in the PDE3A promoter regulates cAMP-induced PDE3A gene expression in patients treated with PDE3i. This molecular mechanism may explain response heterogeneity to this drug class, and may inform a pharmacogenetic strategy for a more effective use of PDE3i in HF.
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