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

Autor:	Morihara, Hirofumi, Yamamoto, Tsuyoshi, Oiwa, Harunori, Tonegawa, Kota, Tsuchiyama, Daisuke, Kawakatsu, Ikki, Obana, Masanori, Maeda, Makiko, Mohri, Tomomi, Obika, Satoshi, Fujio, Yasushi, Nakayama, Hiroyuki
Předmět:	HEART failure treatment PHOSPHOLAMBAN CARDIAC contraction CELL metabolism HEART metabolism HEART ventricle diseases ANIMAL experimentation BIOLOGICAL models BLOOD pressure CALCIUM-binding proteins CELLS CONVALESCENCE EPITHELIAL cells LEFT heart ventricle HEART physiology HEART failure HYPERTENSION INTRAVENOUS injections MICE NUCLEOTIDES TIME LEFT ventricular hypertrophy
Zdroj:	Journal of Cardiovascular Pharmacology & Therapeutics; May2017, Vol. 22 Issue 3, p273-282, 10p
Abstrakt:	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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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