Inhibition of miR-154 protects against cardiac dysfunction and fibrosis in a mouse model of pressure overload

Bianca C. Bernardo, Sally S. Nguyen, Xiao-Ming Gao, Yow Keat Tham, Jenny Y. Y. Ooi, Natalie L. Patterson, Helen Kiriazis, Yidan Su, Colleen J. Thomas, Ruby C. Y. Lin, Xiao-Jun Du, Julie R. McMullen

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Abstract

Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.
Original languageEnglish
Article number22442
Number of pages12
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 1 Mar 2016

Keywords

  • cardiac hypertrophy
  • miRNAs

Cite this

Bernardo, B. C., Nguyen, S. S., Gao, X-M., Tham, Y. K., Ooi, J. Y. Y., Patterson, N. L., Kiriazis, H., Su, Y., Thomas, C. J., Lin, R. C. Y., Du, X-J., & McMullen, J. R. (2016). Inhibition of miR-154 protects against cardiac dysfunction and fibrosis in a mouse model of pressure overload. Scientific Reports, 6, [22442]. https://doi.org/10.1038/srep22442