Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure

Circ Heart Fail. 2020 Mar;13(3):e006298. doi: 10.1161/CIRCHEARTFAILURE.119.006298. Epub 2020 Mar 12.


Background: MicroRNAs are small, noncoding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant microRNA expression contributes to the heart failure (HF) phenotype; however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action of microRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF.

Methods and results: We found that microRNA-152 (miR-152) expression was upregulated in the failing human heart and experimental animal models of HF. Transgenic mice with cardiomyocyte-specific miR-152 overexpression developed systolic dysfunction (mean difference, -38.74% [95% CI, -45.73% to -31.74%]; P<0.001) and dilated cardiomyopathy. At the cellular level, miR-152 overexpression perturbed mitochondrial ultrastructure and dysregulated key genes involved in cardiomyocyte metabolism and inflammation. Mechanistically, we identified Glrx5 (glutaredoxin 5), a critical regulator of mitochondrial iron homeostasis and iron-sulfur cluster synthesis, as a direct miR-152 target. Finally, a proof-of-concept of the therapeutic efficacy of targeting miR-152 in vivo was obtained by utilizing a locked nucleic acid-based inhibitor of miR-152 (LNA 152) in a murine model of HF subjected to transverse aortic constriction. We demonstrated that animals treated with LNA-152 (n=10) showed preservation of systolic function when compared with locked nucleic acid-control treated animals (n=9; mean difference, 18.25% [95% CI, 25.10% to 11.39%]; P<0.001).

Conclusions: The upregulation of miR-152 expression in the failing myocardium contributes to HF pathophysiology. Preclinical evidence suggests that miR-152 inhibition preserves cardiac function in a model of pressure overload-induced HF. These findings offer new insights into the pathophysiology of HF and point to miR-152-Glrx5 axis as a potential novel therapeutic target.

Keywords: heart failure; inflammation; mice; microRNA; phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antagomirs / administration & dosage*
  • Aorta / physiopathology
  • Aorta / surgery
  • Case-Control Studies
  • Disease Models, Animal
  • Gene Silencing*
  • Glutaredoxins / genetics
  • Glutaredoxins / metabolism
  • Heart Failure / genetics
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control*
  • Humans
  • Ligation
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / ultrastructure
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / ultrastructure
  • Proof of Concept Study
  • Stroke Volume
  • Ventricular Function, Left


  • Antagomirs
  • Glrx5 protein, mouse
  • Glutaredoxins
  • MIRN152 microRNA, human
  • MicroRNAs