Dataset Information

A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium.

ABSTRACT:

Background

The 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.

Objectives

The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF.

Methods

PDE3A 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.

Results

The 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.

Conclusions

A 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.

SUBMITTER: Sucharov CC

PROVIDER: S-EPMC6499384 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium.

Sucharov Carmen C CC Nakano Stephanie J SJ Slavov Dobromir D Schwisow Jessica A JA Rodriguez Erin E Nunley Karin K Medway Allen A Stafford Natalie N Nelson Penny P McKinsey Timothy A TA Movsesian Matthew M Minobe Wayne W Carroll Ian A IA Taylor Matthew R G MRG Bristow Michael R MR

Journal of the American College of Cardiology 20190301 10

<h4>Background</h4>The 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.<h4>Objectives</h4>The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF.<h4>Methods</h4>PDE3A promoter ...[more]

PMID: 30871701

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Dataset Information

A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium.

Background

Objectives

Methods

Results

Conclusions

Publications

A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium.

Similar Datasets

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