Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure.
Adrenergic beta-Agonists
/ pharmacology
Animals
Cyclic AMP
/ metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4
/ genetics
Disease Models, Animal
Disease Susceptibility
Gene Expression
Genetic Therapy
Genetic Vectors
/ genetics
Heart Failure
/ diagnosis
Heart Function Tests
Humans
Isoproterenol
/ pharmacology
Mice
Mice, Transgenic
Myocardium
/ metabolism
Myocytes, Cardiac
/ drug effects
Phenotype
Receptors, Adrenergic, beta
/ metabolism
Transduction, Genetic
Ventricular Remodeling
/ drug effects
cardiac remodeling
cyclic AMP
genetic therapy
heart failure
phosphodiesterase 4
transgenic mice
Journal
Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763
Informations de publication
Date de publication:
14 07 2020
14 07 2020
Historique:
pubmed:
9
4
2020
medline:
31
8
2021
entrez:
9
4
2020
Statut:
ppublish
Résumé
The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.
Sections du résumé
BACKGROUND
The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca
METHODS
We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca
RESULTS
PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca
CONCLUSIONS
Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.
Identifiants
pubmed: 32264695
doi: 10.1161/CIRCULATIONAHA.119.042573
doi:
Substances chimiques
Adrenergic beta-Agonists
0
Receptors, Adrenergic, beta
0
Cyclic AMP
E0399OZS9N
Cyclic Nucleotide Phosphodiesterases, Type 4
EC 3.1.4.17
PDE4B protein, human
EC 3.1.4.17
Isoproterenol
L628TT009W
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
161-174Commentaires et corrections
Type : CommentIn
Type : CommentIn