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Knockdown of mechanosensitive miRNA cluster—miR‐106b~25 decreases endothelial proliferation and prevents atherosclerosis in ApoE −/− mice
Author(s) -
Kumar Sandeep,
Jo Hanjoong
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.165.1
Subject(s) - mechanosensitive channels , gene knockdown , biology , microrna , downregulation and upregulation , microbiology and biotechnology , medicine , genetics , gene , receptor , ion channel
Atherosclerosis is the underlying cause of cardiovascular events, such as heart attack and stroke. The disease preferentially occurs in arterial regions exposed to disturbed flow (d‐flow) , in part, due to alterations in endothelial gene expression. Emerging evidence indicates that alteration of flow conditions regulate expression of small, noncoding RNAs (miRNAs) in endothelial cells. Here, using a partial carotid ligation model of d‐flow induced atherosclerosis, we identified a highly conserved, flow‐sensitive miRNA cluster, miR‐106b‐93‐25, that is upregulated in the carotid endothelium that experienced d‐flow for 48 hours. Additional studies using endothelial‐enriched RNAs from the lesser‐ (chronic d‐flow region) and greater curvature (chronic s‐flow region) of aortic arch further validate the increased expression of 106b‐93‐25 in the chronic d‐flow regions. Using arterial endothelial cells from human and mouse and a cone‐and‐plate shear device, we found that expression of miR‐106b‐93‐25 increases in the endothelial cells exposed to oscillatory shear stress (OS) for 24 h. In silico and subsequent wet‐lab target identification studies showed that this miRNA cluster targets the inhibitors of cell cycle regulators, cyclin‐dependent kinase inhibitors (CDKIs). Studies including gain‐of‐function (pre‐miR‐106b, ‐93 and ‐25) and loss‐of‐function (anti‐miR‐106b, ‐93 and ‐25) approaches showed that this miRNA cluster downregulates the CDKN1A and CDKN1B in a flow‐dependent manner. Using our mouse partial carotid ligation model of d‐flow induced atherosclerosis, we demonstrated that genetic knockdown of mechanosensitive miRNA cluster—miR‐106b~25 using heterozygous miR‐106b~25 +/− mice on ApoE background prevents atherosclerosis development in comparison to the age‐matched littermate controls. Our results suggest that targeting mechanosensitive miRNA cluster using anti‐miRNA‐based approaches may provide a new treatment strategy for atherosclerosis. Support or Funding Information SK received an American Heart Association postdoctoral award to carry out the research work.Knockdown of miR‐106b‐93‐25 in ApoE KO mice inhibits atherosclerosis development in partial carotid ligation model of atherosclerosis