Plant MIR156a Inhibits Adhesion Of Monocyte To Endothelial Cells By Down-regulating JAM-A

Atherosclerosis is a chronic inflammatory disease that is the leading cause of death from cardiovascular disease.In renct years,although advances in diagnosis,prevention and treatment have improved the life expectancy of atherosclerosis patients,atherosclerosis remains a major health problem all over the world.Atherosclerosis originates from the excessive accumulation of lo w-density lipoprotein(LDL)in the vascular endothelium.The accumulated LDL is easily oxidized to oxidized low-density lipoprotein(ox-LDL),which induces endothelial cell activation and expression of pro-inflammatory genes.At the same time,it promotes the expression of various adhesion molecules on endothelial cells.Junction adhesion molecule-A(JAM-A)is a member of the immunoglobulin superfamily transmembrane adhesion molecules,which maintains the integrity of tight junctions through homophilic interactions.Under inflammatory conditions,activation of endothelial cells causes JAM-A to re-migrate to the surface of endothelial cells,promoting adhesion of monocytes,T cells,and migration across cells.MicroRNAs are small RNAs that function as guide molecules in RNA silencing by base pairing with their target mRNAs.At 19-25 nucleotides long,miRNAs are almost the shortest functional eukaryotic noncoding RNAs.They mediate post-transcriptional changes in gene expression usually through binding to the 3'untranslated region(3'-UTR)of target mRNAs with their seed region.MicroRNAs have become the spotlight of the biological community for more than a decade,but we are only now beginning to understand their functions.The detection of stably expressed endogenous microRNAs in human blood suggests that these circulating miRNAs can mediate intercellular communication.Our previous study find that exogenous rice MIR168a could regulate liver low-density lipoprotein receptor adapter protein 1 gene expression in mice.At present,dietary intervention is the safest strategy for preventing cardiovascular disease.It is well known that foods provide fat,carbohydrates,proteins,vitamins,minerals and trace elements.Over the past decades,it has become realized that plants and animal foods also contain considerable amounts of nucleotides,although their effectiveness in humans remains unclear.Here,we show that plant MIR156a,which is abundantly expressed in dietary green veggies,also stably presents in healthy human serum.As we all know,a high dietary intake of green vegetables is associated with reduced risk of many chronic diseases,including atherosclerosis.Compared with age-matched individuals,decreased levels of MIR156a are observed both in serum and blood vessel of cardiovascular disease patients.Bioinformatics analysis predicts that JAM-A is a potential target gene for plant MIR156a.In vitro studies demonstrate that MIR156a can directly target JAM-A,which is up-regulated in atherosclerotic lesions from cardiovascular disease patients.In vitro functional studies demonstrated that ectopic expression of plant MIR156a in human aortic endothelial cells reduced inflammatoryinduced monocytes adhesion by suppressing JAM-A,thus suppressing the progression of atherosclerosis.Taken together,these findings offer a novel vasoprotective molecular mechanism of green veggies through plant microRNAs and a new perspective for the cross-kingdom communication of miRNAs.Moreover,it is adding new dimensions to dietary herbal medicine development.