The Study Of Metalloproteinase ADAMTS18 In Phenotypic Transformation Of Vascular Smooth Muscle Cells

Background:Atherosclerosis is the primary cause of mortality and a common pathogenesis for cardiovascular disease.Recent evidence indicates that 70% of all cells in the atherosclerotic lesions are derived from vascular smooth muscle cells(VSMCs),which exhibited a greater synthetic capacity for extracellular matrix,proteases,and cytokines.Previously,we found that Adamts18 KO mice demonstrated significantly incrassated vascular media in common carotid artery(CCA)compared to WT mice.Furthermore,Adamts18 knockout(KO)mice are easier to develop atherosclerosis than WT mice after high-fat diet,and ADAMTS18 deficiency promotes atherosclerosis in apolipoprotein E-deficient mice.However,the underlying mechanisms is remain unclear.Methods:In this study,we used Adamts18 KO mouse model combined with proteomic approach to investigate the potential molecule mechanisms.Results:1.ADAMTS18 deficiency promotes VSMC phenotypic switching.The expressions of VSMC differentiation(contractile)markers(e.g.?-SMA,and SM-MHC)were significantly reduced in CCA of Adamts18 KO mice compared to that in WT controls.In contrast,expressions of synthetic(noncontractile)markers(e.g.OPG)were significantly increased in CCA of Adamts18 KO mice.Western blotting analysis further confirmed that proliferating cell nuclear antigen(PCNA),a reliable biomarker for evaluation of cell proliferation,and serum response factor(SRF)were increased in CCA of Adamts18 KO mice when compared to those of WT control.2.A number of 1250 proteins were identified in this study by proteomic approach.We found that the abundance of 77 CCA proteins was significantly different between KO and WT,which is associated with altered microRNA.3.IPA analysis showed that mature microRNA,such as miR-542-3p(z-scores=-2),miR-133a-3p(z-scores=-2.425),miR-3175(z-scores=-2.219)were significantly down regulated in CCA of Adamts18 KO mice compared to WT mice.These micro-RNAs are highly associated with VSMC proliferation and calcification.Conclusion:ADAMTS18 deficiency contributes to VSMC phenotypic switch in CCA of Adamts18 KO mice and promotes the progress of atherosclerosis,which is associated with down-regulation of micro-RNA,especially miR-133.