Phospholamban Inhibition by a Single Dose of Locked Nucleic Acid Antisense Oligonucleotide Improves Cardiac Contractility in Pressure Overload-Induced Systolic Dysfunction in Mice.
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.



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%.



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.
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Hirofumi
H
Morihara
2 Laboratory of Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Tsuyoshi
T
Yamamoto
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Harunori
H
Oiwa
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Kota
K
Tonegawa
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Daisuke
D
Tsuchiyama
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Ikki
I
Kawakatsu
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Masanori
M
Obana
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Makiko
M
Maeda
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Tomomi
T
Mohri
2 Laboratory of Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Satoshi
S
Obika
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Yasushi
Y
Fujio
1 Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Hiroyuki
H
Nakayama
D000818:Animals; D001794:Blood Pressure; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D022781:Hepatocytes / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D020127:Recovery of Function; D013599:Systole / Q000187:drug effects*; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D000099211:Phospholamban; C477371:locked nucleic acid
heart failure; oligonucleotide therapeutics; phospholamban