2017年5月
Phospholamban Inhibition by a Single Dose of Locked Nucleic Acid Antisense Oligonucleotide Improves Cardiac Contractility in Pressure Overload-Induced Systolic Dysfunction in Mice
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS
- 巻
- 22
- 号
- 3
- 開始ページ
- 273
- 終了ページ
- 282
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1177/1074248416676392
- 出版者・発行元
- SAGE PUBLICATIONS INC
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 and Results: 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.
Methods and Results: 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.
- リンク情報
-
- DOI
- https://doi.org/10.1177/1074248416676392
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/27811197
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000398836500009&DestApp=WOS_CPL
- URL
- https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85018762172&origin=inward
- ID情報
-
- DOI : 10.1177/1074248416676392
- ISSN : 1074-2484
- eISSN : 1940-4034
- PubMed ID : 27811197
- SCOPUS ID : 85018762172
- Web of Science ID : WOS:000398836500009