The Effect Of SUMOylated PPARγ In The Regulation Of Diabetesmellitus Accelerated Atherosclerosis

Background:Diabetes mellitus(DM)could accelerate atherosclerosis by activating NF-κB and downstream inflammation.SUMOylation is a kind of post-tanslational modification of protein which could inhibit NF-κB and downstream inflammation after combining with PPARy,a widely expressed transcription factor.Ubc9 is a key enzyme for SUMOylation of PPARy.Recent studies suggested that Ubc9 could be downregulated by high glucose in myocardium and skeletal muscle.We assumed that diabetes mellitus could prompt inflammation and atherosclerosis though inhibiting the SUMOylaiton of PPARγ in vascular and endothelial cells.Methods:Vascular ultrasound and histological tests were used to evaluate vessel injury in the model of type 1 diabetes mellitus(T1DM)and rat carotid artery balloon injury.Western Blot and immunohistochemical staining were used to detect expression of Ubc9 in vascular tissue.SUMOylation Assay Kit was used to evaluate SUMOylation of PPARy.Human umbilical vascular endothelial cells(HUVEC)were cultured in high glucose medium.Real time-RT-PCR and Western Blot were used to testify expression of inflammation genes and Ubc9.Lentivirus with Ubc9 and Rosiglitazone were used to upregulate PPARy SUMOylation in vivo and in vitro.Results:Vascular ultrasound and histological analysis showed DM prompted intimal hyperplasia in balloon injured rat carotid artery.High glucose also upregulated inflammation genes(IL-8,IL-1β)in HUVEC.The expression of Ubc9 and PPARy SUMOylation were downregulated both in vascular tissues and HUVEC in DM group or during high glucose treatment.Upregulation of PPARγ SUMOylation by overexpression of Ubc9 or rosiglitazone alleviated DM prompted inflammation or intimal hyperplasia in vivo and in vitro.Conclusion:DM could inhibit the PPARy SUMOylaiton and prompt inflammation and atherosclerosis in vascular and endothelial cells.Upregulation of PPARy SUMOylaiton though Ubc9 overexpression or rosiglitazone could play a protecting role in DM prompted atherosclerosis.BackgroundEndothelin-1(ET-1)and its receptor has been suggested to be upregulated in high glucose environment which increase the incidence of diabetes related cardiovascular complication.Our previous study demonstrated that oleanolic acid(OA),a naturally occurred compound in fruits and vegetables had ET-1 antagonistic effect.We purpose to verify whether OA could ameliorate DM induced cardiomyocytes injury through antagonism of ET-1 system.MethodsNeonatal rats ventricular cardiomyocytes(NRVMs)were subjected to medium with 25 mM of glucose for the induction of high glucose related cardiomyocytes injury.Natriuretic peptide B(BNP),mitochondrial membrane potential(MMP)and cell surface area were used to evaluate NRVMs injury.mRNA expression of endothelin A receptor(ETA)was detected with qPCR.Human induced induced pluripotent stem cells(iPS)derived cardiomyocytes were used to evaluate ET-1 pathway antagonistic effect of OA in Real Time Cellular Analysis(RTCA)technology.Molecular docking of OA and ETA was performed with Sulflex-Dock program.ResultsHigh glucose could increase the expression of BNP in both mRNA and protein level.Cell surface area and MMP were also increased in high glucose environment.High glucose induced NRVMs injury couldn’t be reversed by hypoglycemic therapy.ETAwas upregulated by stimulation of high glucose and couldn’t be decreased by hypoglycemic therapy.OA could reverse ET-1 induced impairment of beating rate and amplitude in iPS derived cardiomyocytes.Molecular docking showed that OA was docked into the active site of e which further demonstrated the interaction between OA and ETA.OA also could reverse high glucose induced BNP upregulation,enlargement of cell area and MMP.ConclusionHigh glucose induced upregulation of ETA may be one of the reasons of metabolic memory.OA has a protective effect on high glucose induced cardiomyocytes injury through ETA antagonistic function.OA could be a potential drug for diabetes related cardiovascular complication.Background:Peri-strut low-intensity area(PLIA)is a typical image pattern of neointima detected by optical coherence tomography(OCT)after stent implantation.However,few studies evaluated the predictors and prognosis of it,therefore,we aimed to explore the genesis and prognosis of PLIA detected by OCT in the present study.Methods:Patients presenting neointimal hyperplasia documented by OCT reexamination after percutaneous coronary intervention(PCI)were prospectively included from 2009 to 2011.Peri-strut intensity was analyzed and classified into two patterns:low intensity and high intensity.Clinical characteristics were analyzed in order to assess their contribution to peri-strut intensity patterns.Follow-up were performed in patients who didn’t receive revascularization during OCT reexamination and the prognosis of the patients was evaluated.Results:There were 128 patients underwent OCT reexamination after stent implantation included in the study.PLIA was detected in 22(17.2%)patients.The incidence of PLIA was positively correlated with serum triglyceride(odds ratio[OR]:2.11,95%CI:1.14-3.90,P=0.017),low density lipoprotein(OR:2.61,95%CI:1.22-5.66,P=0.015),history of cerebrovascular disease(OR:101.11,95%CI:6.54-1562.13,P<0.001)and initial clinical presentation of acute coronary syndrome(ACS,OR:18.77,95%CI:2.73-128.83,P=0.003),while negatively correlated with stent implantation time(OR:0.57,95%CI:0.33-0.98,P=0.043).The median follow-up was longer than 3.8 years.Major adverse cardiovascular events(MACEs)occurred in 7(7.3%)patients while showed no correlation with PLIA.A total of 17(17.7%)patients experienced unstable angina(UA)and showed significant correlation with PLIA(hazard ratio[HR]:6.16,95%CI:1.25-30.33,P=0.025).Conclusion:PLIA detected by OCT was positively correlated with higher serum lipid level,history of cerebrovascular disease and initial presentation of ACS,and negatively correlated with stent implantation time.Patients with PLIA were more likely to have UA than those with high intensity while no significant difference was found in MACEs between the two groups..