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.
Funding
This study was funded by National Health and Medical Research Council Project Grant 586603 (to J.R.M. and R.C.Y.L.), and also supported in part by the Victorian Government's Operational Infrastructure Support Program. X.J.D. and J.R.M. are National Health and Medical Research Council Senior Research Fellows (1043026 and 586604, 1078985). J.R.M. and R.C.Y.L. were also supported by an Australian Research Council Future Fellowship (FT0001657), and a University of New South Wales Vice Chancellor Research Fellowship, respectively.
History
Publication Date
2016-03-01
Journal
Scientific Reports
Volume
6
Issue
1
Article Number
22442
Pagination
12p.
Publisher
Nature Publishing Group
ISSN
2045-2322
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