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

Morihara, Hirofumi; Yamamoto, Tsuyoshi; Oiwa, Harunori; Tonegawa, Kota; Tsuchiyama, Daisuke; Kawakatsu, Ikki; Obana, Masanori; Maeda, Makiko; Mohri, Tomomi; Obika, Satoshi; Fujio, Yasushi; Nakayama, Hiroyuki

doi:10.1177/1074248416676392

Cited by 9 publications

(11 citation statements)

References 48 publications

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“…Reductions in SERCA2 expression/activity or enhancement of the inhibitory effects of PLN are also hallmarks of heart failure (HF) (65,66). Interestingly, PLN inhibition has been shown to alleviate cardiomyopathy in several animal models and improve cardiomyocyte contractility in patients with HF (67)(68)(69). Here, we show that decreased Pln dose can rescue the arrhythmogenic phenotype caused by Tbx5 haploinsufficiency, by restoring SERCA function and normalizing SR Ca 2+ content (Figures 4 and 6 previously described (17).…”

Section: Discussionsupporting

confidence: 56%

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Laforest¹,

Dai²,

Tyan³

et al. 2019

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 56%

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Laforest¹,

Dai²,

Tyan³

et al. 2019

Journal of Clinical Investigation

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“…ASOs have recently achieved clinical success in ameliorating diseases such as spinal muscular atrophy, transthyretin (TTR) amyloidosis, and hyperlipidemia 20 . Improvements in ASO potency and delivery through advances in medicinal chemistry offer the potential to target tissues beyond the liver such as skeletal muscle and heart [21][22][23] . A previous report showed cardiac PLN downregulation and short-term improvements in cardiac contractility following hydrodynamic intravenous delivery of a locked nucleic acid (LNA)-modified gapmer ASO targeting PLN in mice with pressure overload induced HF 23 .…”

mentioning

confidence: 99%

Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

et al. 2021

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Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca2+ handling is a key feature of HF pathophysiology. Restoring the Ca2+ regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp−/−), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF.

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“…Antisense ODNs directed against leukemia inhibitory factor (LIF) and cardiotrophin-1 were successful in downregulating angiotensin II-induced cardiac hypertrophy in vitro [ 40 ]. Moreover, a single systemic administration of antisense ODNs targeting phospholamban, a SERCA2a inhibitor, dramatically improved contractility in a pressure overload model of heart failure [ 34 ]. In addition, decreasing NF-κB target genes ameliorated cardiac remodeling associated with ischemia [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure

et al. 2021

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Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach.

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

Abstract: 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.

Cited by 9 publications

References 48 publications

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis

Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

AAV-mediated expression of NFAT decoy oligonucleotides protects from cardiac hypertrophy and heart failure

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