Phospholamban Inhibition by a Single Dose of Locked Nucleic Acid Antisense Oligonucleotide Improves Cardiac Contractility in Pressure Overload-Induced Systolic Dysfunction in Mice
| Autor: | Daisuke Tsuchiyama, Ikki Kawakatsu, Makiko Maeda, Kota Tonegawa, Masanori Obana, Satoshi Obika, Hiroyuki Nakayama, Hirofumi Morihara, Yasushi Fujio, Tomomi Mohri, Harunori Oiwa, Tsuyoshi Yamamoto |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Time Factors Systole Oligonucleotides Blood Pressure 030204 cardiovascular system & hematology Pharmacology Ventricular Function Left Contractility 03 medical and health sciences Ventricular Dysfunction Left 0302 clinical medicine Medicine Animals Pharmacology (medical) Myocytes Cardiac Locked nucleic acid Strong binding Pressure overload Heart Failure Nuclease biology business.industry Myocardium Calcium-Binding Proteins Recovery of Function Oligonucleotides Antisense medicine.disease Phospholamban Mice Inbred C57BL Disease Models Animal 030104 developmental biology Heart failure Antisense oligonucleotides Hypertension Injections Intravenous biology.protein Hepatocytes Hypertrophy Left Ventricular Cardiology and Cardiovascular Medicine business |
| Zdroj: | Journal of cardiovascular pharmacology and therapeutics. 22(3) |
| ISSN: | 1940-4034 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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