MicroRNAs are short non-coding RNAs that regulate gene expression by base-paring with the 3’UTRs of target mRNAs. Several microRNA were previously implicated in the pathogenesis of atherosclerosis.
The aim of this study was to gain an understanding of the possible role of the miR-106b~25 microRNA cluster in regulating atherosclerosis in mice.
To test the effect of miR-106b~25 deletion on atherosclerosis, miR-106b~25 knockout mice were outcrossed into ApoE knockout background to generate double knockout mice. At 9 month of age, atherosclerosis levels were evaluated in the aortic sinus of ApoE knockout and double knockout mice by oil-red-O staining. Lesion size was 2-fold smaller in double KO mice in comparison to ApoE KO mice.In addition, collagen staining by masson-trichrome showed a trend towards a stable plaque phenotype in the double KO mice. Lipid profiling of plasma samples of double KO and ApoE KO mice using FPLC revealed an over 2-fold decrease in VLDL cholesterol content and a 50% decrease in LDL cholesterol content in double KO mice. However, there was no change in HDL or triglyceride levels.By using target prediction software, we have identified several possible targets for the miR-106b~25 cluster including the VLDL and LDL receptors. By real-time PCR analysis we found that upon feeding miR-106b~25 KO mice with high fat diet, the expression of LDL and VLDL receptors was higher than in the wild-type mice, suggesting the miR-106b~25 cluster regulates atherosclerosis by influencing clearance of VLDL and LDL from the plasma.
In conclusion, the miR-106b~25 cluster was shown here to regulate atherosclerosis progression. In the future, inhibition of miR-106b~25 may serve as novel therapeutic approach for management of plasma cholesterol levels.
