| Aims1)Serum uric acid(SUA)is closely associated with multiple cardiovascular risk factors such as obesity.However,the associations of SUA with atherosclerosis(AS)and its complications remain controversial.Our aim was to explore the associations among SUA,obesity and cardio-cerebrovascular events(CCEs)in Chinese inpatients with type 2 diabetes(T2DM).2)We also investigated effect of FAM172A and chaetocin on vascular smooth muscle cells(VSMCs)proliferation,migration and phenotypic switching so as to further explore the potential molecular targets of AS.Methods1)This cross-sectional study was carried out in 2962 inpatients with T2DM.The subjects were stratified into quartile based on SUA levels.Obesity was defined as body mass index(BMI)≥25 kg/m~2.Severe obesity was defined as BMI≥35 kg/m~2.CCEs were defined as a history of transient ischemic attack,ischemic stroke,hemorrhagic stroke,angina,myocardial infarction,angioplasty or coronary artery bypass surgery.Both obesity and CCEs were compared among SUA quartile groups,respectively.2)Fam172a-/-Apoe-/-mice and littermates Fam172a+/+Apoe-/-mice were constructed,and fed with western diet to induce AS.The effects of Fam172a on blood lipid profile,AS progression,plaque stability and VSMCs phenotypic switching were analyzed.Fam172a overexpression and knockdown Movas stable cell lines were constructed to analyze the effects of Fam172a on VSMCs proliferation,migration and phenotypic switching.3)The effects of chaetocin on VSMCs proliferation,migration and phenotypic switching of Movas and A7r5 cells were analyzed.Ch IP-q PCR was applied to analyze the effect of chaetocin on on VSMCs contractile gene promoters’Histone H3 lysine 9trimethylation(H3K9me3)modification.ResultsAfter controlling for sex,age and diabetic duration(DD),there were significant increases in the prevalence of both obesity(32.6%,41.9%,50.1%,and 62.8%,respectively,p<0.001 for trend)and severe obesity(0.4%,0.6%,0.8%,and 1.3%,respectively,p<0.001 for trend)across the SUA quartiles.A fully adjusted multiple logistic regression analysis revealed that SUA quartiles were independently associated with the presence of obesity(p<0.001).The prevalence of CCEs was obviously higher in the obese patients than in the nonobese patients(16.8%vs 13.2%,p=0.027).After controlling for multiple confounding factors,BMI levels were also significantly correlated with the presence of CCEs(p=0.020).However,there was no significant association of SUA quartiles/SUA levels with the presence of CCEs in type 2 diabetes.Fam172a-/-did not change cholesterol,triglyceride,HDL and LDL levels of AS mice induced by western diet.Moreover,Fam172a-/-increased AS burden,and reduced plaque stability.And Fam172a-/-also promoted VSMCs phenotypic switching in AS mice induced by western diet.In vitro,Fam172a overexpression promoted VSMCs proliferation and migration,and inhibited VSMCs phenotypic switching.Fam172a knockdown inhibited VSMCs proliferation and migration,and promoted VSMCs phenotypic switching.The effect of chaetocin on the VSMCs proliferation was concentration-and time-dependent.And chaetocin inhibited VSMCs migration and phenotypic switching.And chaetocin down-regulated H3K9me3 modification enrichment level in VSMCs constractile gene promoters.Conclusions1)SUA levels were independently associated with obesity but not with CCEs in hospitalized Chinese patients with T2DM.In selected populations such as subjects with T2DM,the role of uric acid in cardiovascular complications might be attributable to other cardiovascular risk factors,such as obesity.2)Fam172a knockout increased AS burden and reduced plaque stability.And Fam172a knockout promoted AS progression independent of handling serum lipids.Fam172a promoted VSMCs proliferation and migration,and inhibited VSMCs phenotypic switching.3)Chaetocin inhibited VSMCs proliferation,migration and phenotypic switching,which may be attributed to the down-regulation of H3K9me3 modification in VSMCs contractile gene promoters. |
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