The Effect And Mechanism Of Atrial Natriuretic Peptide On Macrophage ABCA1/G1 Mediated Cholesterol Efflux

ObjectiveIt has been reported that atrial natriuretic peptide（ANP）regulates lipid metabolism by stimulating adipocyte browning,lipolysis,lipid oxidation,and influencing the secretion of adipokines.In our previous study,we found that the plasma NT-pro ANP concentration of hypertensive disorders of pregnancy（HDP）was significantly increased compared with those of normotensive pregnancy.Alterations of maternal serum lipids at late gestation can affect pregnant outcome and neonatal adverse prognostic.Thus,the objective was to investigate the effects of ANP on the ABCA1-and ABCG1-mediated cholesterol efflux in THP-1 macrophages.Thus,we aim to found the role of ANP in the regulation of lipid metabolism in HDP.MethodsThere were 265 HDP patients and 178 normotensive pregnant women as control group were recruited in the First Affiliated Hospital of XXX.The clinic demographic characteristics and laboratory profile of study population were collected.Plasma total triglycerides（TG）,total cholesterol（TC）,low-density cholesterol（LDL-C）,and high-density cholesterol（HDL-C）were compared between different groups.Statistical analysis was conducted.THP-1 monocytes were differentiated into macrophages by exposed to phorbol12-myristate-13-acetate（PMA）,and then incubated with different concentrations of ANP.ATP binding cassette transporter A1（ABCA1）and ATP binding cassette transporter G1（ABCG1）m RNA were evaluated by quantitative real-time polymerase chain reaction（q RT-PCR）.ABCA1 and ATP ABCG1 protein were evaluated by western blot.The effect of ANP on cholesterol uptake was observed by NBD-cholesterol fluorescence labeling.ABCA1 and ABCG1 mediated cholesterol efflux to apolipoprotein A-I（apo A-I）and HDL respectively from THP-1-derived macrophages were measured by NBD-cholesterol fluorescence intensity.Meanwhile,natriuretic peptide receptor A（NPRA）si RNA and specific agonists of peroxisome proliferator-activated receptorγ（PPARγ）and liver X receptorα（LXRα）were studied to investigate the mechanism involved.ResultsClinical sample results shows that plasma TG,TC,LDL-C,LDL-C/HDL-C were significantly increased in HDP group（each P<0.01）.Plasma HDL-C was significantly decreased in HDP group compared with that of control（P<0.01）.In vitro,the effect of ANP on macrophages was observed.And ANP in the concentration of 10^-9-10^-5mol/L inhibited the transcription of ABCA1 and ABCG1 m RNA in a dose-dependent way.ANP in the concentration of 10^-9-10^-5mol/L inhibited the expression of ABCA1 and ABCG1 protein in a dose-dependent way.Meanwhile,ANP accelerated cholesterol uptake in THP-1-derived macrophages.ANP treatment also inhibited the function of ABCA1 mediated cholesterol efflux to apolipoprotein A-I and the function of ABCG1mediated cholesterol efflux to HDL.In addition,ANP decreased the expression of PPARγand LXRαin macrophages.NPRA si RNA and PPARγand LXRαspecific agonists partially reversed the inhibition of PPARγand LXRαprotein expression by ANP.NPRA si RNA and PPARγand LXRαspecific agonists partially reversed the inhibition of ABCA1 and ABCG1 protein expression by ANP.The above results indicate that ANP binding to its type A receptor inhibited ABCA1 and ABCG1expression through inhibiting the PPARγand LXRαpathway.This mechanism may be related to the increased of ANP and the decreased of HDL-C in HDP.ConclusionsANP binding to its type A receptor inhibited ABCA1/G1 expression through PPARγ/LXRαpathway in THP-1 macrophages and the function of ABCA1 and ABCG1mediated cholesterol efflux was also impaired.This may provide a new mechanism of the decreased HDL-C in hypertensive pregnant patients.