Effects Of β3-AR Agonist Of HepG2 Cells On Lipid-loading Process Of Foam Cells And Comparison Of The Cardiovascular Risk Factors Control Status Between PCI And CABG Patients

Background Cardiovascular and cerebrovascular diseases caused by atherosclerosis(AS)are the leading causes of death.The formation of foam cells is not only one of the early signs of AS,but is also a key step in the genesis and development of AS.The main reason for the formation of foam cells is imbalances in the cholesterol inflow and outflow within macrophages.Promoting lipid efflux from macrophages might be an effective way to inhibit foam cell formation and delay the occurrence and development of atherosclerotic lesions.Reverse cholesterol transport(RCT)is defined as transporting cholesterol from peripheral tissues and cells to the liver for further metabolism.This process involves cholesterol efflux from macrophage-derived foam cells to acceptors out of the cells,such as high-density lipoprotein(HDL).How to promote RCT in macrophage has recently become a new focus of anti-AS research.Previous studies have shown that β3-adrenoceptor(β3-adrenoceptor)can be considered as a receptor that mediate metabolism in adipose tissue.It has also been detected in the heart,brain,lungs,and liver.We previously found that β3-adrenoceptor agonist showed protective effects on atherosclerosis development in Apo E-/-mice,and that β3-adrenoceptor activation significantly ameliorated lipid metabolism disorders and increased plasma HDL levels in Apo E-/-mice.However,the mechanisms needs to be further addressed.In the current study,we explored the role and molecular mechanisms of hepatocytes’ secretion on the cholesterol efflux of macrophage-derived foam cells.By culturing ac-low density lipoprotein(LDL)loaded RAW264.7 cells with the supernatants from β3-adrenoceptor agonist treated Hep G2 cells,we demonstrated that β3-adrenoceptor activation induced secretion of apolipoprotein A-I(Apo A-I),the major component of prebeta HDL,by hepatocytes promotes foam cell cholesterol efflux.This may be mainly involved in the in vivo anti-atherosclerosis effect ofβ3-adrenoceptor activation.Objective To explore the effects of β3-adrenoceptor(β3-AR)activation on Hep G2 cells and its influence on cholesterol efflux from macrophage foam cells.Methods Hep G2 cells were cultured and treated with the β3-AR agonist,BRL37344,and antagonist,SR52390 A,and the expression of apolipoprotein A-I(Apo A-I),Apo A-II,Apo B,and β3-AR in the supernatants and cells was determined.Peroxisome proliferator-activated receptor(PPAR)γ and PPARα expression in the Hep G2 cells was also assessed.Next,using the RAW264.7 macrophage foam cells model,we also assessed the influence of the Hep G2 cell supernatants on lipid efflux.The cholesterol content of the foam cells was also measured,and the cholesterol efflux from the macrophages was examined by determining 3H-labeled cholesterol levels.ABCA1 and ABCG1 expression of the macrophages foam cells was also assessed.Results 1.The concentration of Apo A-I significantly increased after BRL37344 treatment(BRL37344 group)and significantly decreased after SR59230 A treatment(SR59230A group)compared to that in the control group(P < 0.01).In contrast,the Apo A-II level in the BRL37344 group was significantly lower compared to that in the control(P < 0.05)and the SR59230A(P < 0.05)groups.Apo B levels were not significantly different between the three groups(P > 0.05).2.Compared with the control group,the BRL37344 group showed significantly higher Apo A-I m RNA expression(P < 0.01)and the SR59230 A group showed significantly lower Apo A-I m RNA expression(P < 0.01).In contrast,Apo A-II m RNA expression in the BRL37344 group was significantly lower compared to that in the control group(P < 0.01)and the SR59230 A group(P < 0.01).However,Apo B m RNA expression was not significantly different between the three groups(P > 0.05).Apo A-I,Apo A-II and Apo B protein expression were similar with the m RNA expression in each group.3.BRL37344 treatment significantly elevated PPARγ(P < 0.01)expression but not PPARα expression(P > 0.05),whereas SR59230 A treatment had the opposite effect(P < 0.01).Moreover,compared with the control group,the BRL37344 group showed significantly elevated Apo A-I protein expression(P < 0.01).The upregulation of Apo A-I protein expression by BRL37344 was significantly impeded by GW9662(a PPARγ antagonist)(P < 0.01).4.Compared with the supernatants of the control Hep G2 cells,the supernatants of the BRL37344-treated Hep G2 cells significantly reduced the intracellular levels of TC and CE but increased FC levels in the lipid-loaded RAW264.7 cells.Cholesterol efflux rates also significantly increased in the macrophages treated with supernatants from the BRL37344 group compared with that in the other groups(P < 0.01).5.Treatment with the supernatants of the BRL37344-treated Hep G2 cells significantly upregulated ABCA1 protein levels in the lipid-loaded RAW264.7 cells(P<0.01),but had no effect on the protein expression of ABCG1(P > 0.05).Conclusion 1.β3-AR activation can up-regulate Apo A-I expression in Hep G2 cells;2.β3-AR activation can up-regulate PPARγ expression in Hep G2 cells;3.The increased Apo A-I expression might in a PPARγ-dependent way in Hep G2 cells;4.β3-adrenoceptor-activated Hep G2 cells enhances cholesterol efflux of foam cells;5.The supernatants from Hep G2 cells with BRL37344 stimulation promotes the cholesterol efflux of macrophage-derived foam cells through ABCA1 related pathway.Background The use of secondary prophylactic drugs can bring clinical benefit to patients with coronary revascularization.However,data are scarce regarding secondary preventive drugs utilization,cardiovascular risk factors management,and clinical outcome disparities between patients treated with percutaneous coronary intervention(PCI)and those treated with coronary artery bypass(CABG).Objective To investigate whether there are differences in cardiovascular risk factors control and the prognosis between PCI and CABG patients.Methods We retrospectively reviewed the data of patients admitted to Beijing Anzhen Hospital between January 1,2014 and June 31,2014 who underwent PCI or CABG retrieved from a clinical records database.Results 1.Compared with the CABG group,LDL-C < 1.8 mmol/L,LDL-C < 2.07 mmol/L and BP < 140/90 mm Hg goal achievement rates in the PCI group were significant higher in the unmatched patients after discharge(P <0.01).The FBG and Hb A1 C target attainment rates did not differ significantly between two groups after discharge(P> 0.05).LDL-C <1.8 mmol/L,LDL-C <2.07 mmol/L,BP <140/90 mm Hg,FBG and Hb A1 C goal achievement rates were similar in the propensity matched patients to those of unmatched patients(P> 0.05).2.In unmatched PCI patients,compared with patients who ≥ 60 years old: patients who < 60 years old had better BP < 140/90 mm Hg goal achievement rates and worse LDL-C < 2.07 mmol/L goal achievement rates(P <0.01).In unmatched CABG patients,compared with patients who ≥ 60 years old: patients who < 60 years old had better FBG < 7 mmol/L,Hb A1c<7%,BP < 140/90 mm Hg goals achievement rates(P <0.01).3.In unmatched PCI patients,compared with female: male had better LDL-C <1.8 mmol/L,FBG < 7 mmol/L,and Hb A1c<7% goal achievement rates(P <0.01).The LDL-C < 2.07 mmol/L,and BP < 140/90 mm Hg goal achievement rates were not significantly different(P> 0.05).Those goals achievement rates were not significantly different in CABG patients between female and male(P> 0.05).4.In the propensity matched patients,compared with the CABG group,patients were more likely to take statin,ACEI / ARB,beta-blockers at discharge(P <0.01),proportion of patients taking other lipid lowering drugs ezetimibe and fibrates were higher in the PCI group(P <0.01).There was no significant difference in aspirin use between the two groups(P> 0.05).5.In unmatched patients,composite end point rates were significantly higher in PCI group than in CABG groups(P> 0.05).In propensity matched patients,composite end point rates were not significantly different between two groups(P> 0.05).On multivariable Cox regression analysis,LDL-C < 1.8 mmol/L and HBA1C<7% were independent predictors of composite end points in the unmatched overall,PCI,and CABG patients,hazard ratio were reduced in those patients who achieved goalsConclusion 1.In overall and propensity scores matched patients;lipid and blood pressure goal achievement rates were different between PCI and CABG patients,and the lipid,fasting blood glucose and blood pressure goal achievement rates were not optimistic in either group;2.The lipid,fasting blood glucose and blood pressure goal achievement rates were different between patients who ≥ 60 years old and patients who < 60 years old,female and male in PCI and CABG patients;3.LDL-C < 1.8 mmol/L and HBA1C<7% were significantly associated with reduced risk of composite endpoint events in PCI and CABG patients.