Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure

Rusty L. Montgomery, Thomas G. Hullinger, Hillary M. Semus, Brent A. Dickinson, Anita G. Seto, Joshua M. Lynch, Christianna Stack, Paul A. Latimer, Eric N. Olson, Eva Van Rooij

Research output: Contribution to journalArticlepeer-review

433 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1537-1547
Number of pages11
JournalCirculation
Volume124
Issue number14
DOIs
StatePublished - Oct 4 2011

Keywords

  • gene expression regulation
  • heart failure
  • hypertension
  • hypertrophy
  • microRNAs
  • molecular biology
  • ventricular remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure'. Together they form a unique fingerprint.

Cite this