EZH2 Inhibits Autophagic Cell Death Of Aortic Vascular Smooth Muscle Cells To Affect Aortic Dissection

Enhancer of zeste homolog 2(EZH2),di-and tri-methylating lysine-27 of histone H3,largely functions as transcriptional repressor,and plays critical roles in various kinds of cancers.Here we report a novel function of EZH2 in regulating autophagic cell death(ACD)of vascular smooth muscle cells(VSMCs)to affect aortic dissection(AD).Inhibition of EZH2 activity by UNC1999 or knockdown EZH2 resulted in VSMCs loss,while overexpression of EZH2 facilitated VSMCs growth,and these effects of EZH2 on VSMCs were independent of proliferation and apoptosis.Interesting,more autophagic vacuoles and increased LC3 II protein level were identified in VSMCs with EZH2 inhibition or deficiency.Moreover,compared with counterparts,chloroquine alone or chloroquine with rapamycin treatment were led to more LC3 II accumulated in EZH2 inhibited or knockdown VSMCs,which indicated that EZH2 negatively regulated autophagosome formation.Importantly,ATG5 and ATG7 protein levels were remarkably increased in EZH2 inhibited or deficiency VSMCs,and ATG5 or ATG7 knockdown virtually rescued VSMCs loss induced by EZH2 inhibition or knockdown.In addition,we found that MEK-ERK1/2 signaling pathway,but not AMPKα,mTOR,and AKT pathway,was responsible for the impact of EZH2 on ACD of VSMCs.Furthermore,the adverse effects of EZH2 inhibition or knockdown on VSMCs were largely reversed by PD98059,an inhibitor of MEK1.More importantly,decreased EZH2 expression level in aorta wall of patients with AD indicated its contribution to VSMCs loss and AD occurrence.Taken together,these findings uncovered that EZH2 affects ACD of VSMCs and the pathologic process of AD via regulating ATG5 and ATG7 expression and MEK-ERK1/2 signaling.Our hitherto unrecognized findings indicate that EZH2 activation has therapeutic or preventive potential for AD.