Therapeutic Inhibition of miR-208a Improves Cardiac Function and Survival During Heart Failure

By Rusty L. Montgomery, Thomas G. Hullinger, H. Semus, B. Dickinson, A. Seto, Joshua M. Lynch, C. Stack, Paul A. Latimer, E. Olson, Eva van Rooij. Circulation, 2011

620 citations recorded by the source corpus.

Background— Diastolic dysfunction in response to hypertrophy is a major clinical syndrome with few therapeutic options. MicroRNAs act as negative regulators of gene expression by inhibiting translation or promoting degradation of target mRNAs. Previously, we reported that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac remodeling and upregulation of Myh7 in response to pressure overload. Whether this miRNA might contribute to diastolic dysfunction or other forms of heart disease is currently unknown. Methods and Results— Here, we show that systemic delivery of an antisense oligonucleotide induces potent and sustained silencing of miR-208a in the heart. Therapeutic inhibition of miR-208a by subcutaneous delivery of antimiR-208a during hypertension-induced heart failure in Dahl hypertensive rats dose-dependently prevents pathological myosin switching and cardiac remodeling while improving cardiac function, overall health, and survival. Transcriptional profiling indicates that antimiR-208a evokes prominent effects on cardiac gene expression; plasma analysis indicates significant changes in circulating levels of miRNAs on antimiR-208a treatment. Conclusions— These studies indicate the potential of oligonucleotide-based therapies for modulating cardiac miRNAs and validate miR-208 as a potent therapeutic target for the modulation of cardiac function and remodeling during heart disease progression.

Subfields: Cancer Research, Cardiology and Cardiovascular Medicine, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/93789bd5536375e7dc728bc34a445179c17ddb86

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Citations in the corpus

Development of microRNA therapeutics is coming of age (2014, positive): “Efficacy studies in animal models of heart disease using an LNA-modified antimiR targeting miR-208a indicated that subcutaneous delivery of antimiR-208a prevents disease-related cardiac remodeling, a decline in function, and death during diastolic heart disease (Montgomery et al , 2011).”
MicroRNAs in stress signaling and human disease (2012, background): “Systemic delivery of miR-208a inhibitors delays the onset of cardiac dysfunction in hypertensive rats, confirming the key role of thismiRNA in pathological cardiac remodeling and suggesting the therapeutic potential ofmiR-208a inhibitors in heart disease (Montgomery et al., 2011).”