Phospholamban Inhibition by a Single Dose of Locked Nucleic Acid Antisense Oligonucleotide Improves Cardiac Contractility in Pressure Overload-Induced Systolic Dysfunction in Mice.
J Cardiovasc Pharmacol Ther
; 22(3): 273-282, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-27811197
ABSTRACT
BACKGROUND:
Phospholamban (PLN) inhibition enhances calcium cycling and is a potential novel therapy for heart failure (HF). Antisense oligonucleotides (ASOs) are a promising tool for unmet medical needs. Nonviral vector use of locked nucleic acid (LNA)-modified ASOs (LNA-ASOs), which shows strong binding to target RNAs and is resistant to nuclease, is considered to have a potential for use in novel therapeutics in the next decades. Thus, the efficacy of a single-dose injection of LNA-ASO for cardiac disease needs to be elucidated. We assessed the therapeutic efficacy of a single-dose LNA-ASO injection targeting PLN in pressure overload-induced cardiac dysfunction. METHODS ANDRESULTS:
Mice intravenously injected with Cy3-labeled LNA-ASO displayed Cy3 fluorescence in the liver and heart 24 hours after injection. Subsequently, male C57BL/6 mice were subjected to sham or transverse aortic constriction surgery; after 3 weeks, these were treated with PLN-targeting LNA-ASO (0.3 mg/kg) or scrambled LNA-ASO. Cardiac function was measured by echocardiography before and 1 week after injection. Phospholamban-targeting LNA-ASO treatment significantly improved fractional shortening (FS) by 6.5%, whereas administration of the scrambled LNA-ASO decreased FS by 4.0%.CONCLUSION:
Our study revealed that a single-dose injection of PLN-targeting LNA-ASO improved contractility in pressure overload-induced cardiac dysfunction, suggesting that LNA-ASO is a promising tool for hypertensive HF treatment.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos
/
Sístole
/
Proteínas de Ligação ao Cálcio
/
Oligonucleotídeos Antissenso
/
Função Ventricular Esquerda
/
Disfunção Ventricular Esquerda
/
Insuficiência Cardíaca
/
Miocárdio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article