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

Thomas J. Larocca, Timon Seeger, Maricela Prado, Isaac Perea-Gil, Evgenios Neofytou, Brigham H. Mecham, Mohamed Ameen, Alex Chia Yu Chang, Gaurav Pandey, Joseph C. Wu, Ioannis Karakikes

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish
Pages (from-to)E006298
JournalCirculation: Heart Failure
Issue number3
StatePublished - 1 Mar 2020


  • heart failure
  • inflammation
  • mice
  • microRNA
  • phenotype


Dive into the research topics of 'Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure'. Together they form a unique fingerprint.

Cite this