Relationship Between Blood Pressure,Carotid Intima-media Thickness And Circulating Pcsk9 Concentration

Background and Objectives:Dyslipidemia and hypertension are the well-established risk factors for coronary artery disease.To date it has been demonstrated that elevated serum total cholesterol and low-density lipoprotein cholesterol(LDL-C)levels are associated with an increased risk of new onset of arterial hypertension.Proprotein convertase subtilisin/kexin type 9(PCSK9),a secretory protease produced by the liver,is a major regulator of LDL-C by binding to hepatic LDL receptor(LDLR)and promoting their degradation,thereby leading to increased LDL-C concentrations.However,it remains unclear whether PCSK9 level is associated with blood pressure and carotid intima-media thickness(IMT).Thus,the aim of the present study was to investigate the relationship between PCSK9 and blood pressure and IMT in a large Chinese cohort.Methods:A total of 805 patients without lipid-lowering drugs therapy were consecutively enrolled who were hospitalized in our dyslipidemia division of Fuwai Hospital between October 2012 and October 2014.The baseline characteristics of the participants were collected.Serum PCSK9 levels were measured using a high-sensitivity,quantitative sandwich enzyme immunoassay,and carotid ITM of left and right carotid arteries was assessed by B-mode ultrasound.Firstly,the relationship between blood pressure and PCSK9 was evaluated in hypertensives and normotensives.Furthermore,we examined the relation of PCSK9 to carotid IMT in 256 enrolled patients who had received a carotid ultrasound test.Results:No correlation between PCSK9 and systolic blood pressure(SBP)and diastolic blood pressure(DBP)was found in all enrolled population,hypertensives or normotensives,whereas the level of PCSK9 exhibited a negative association with pulse pressure(PP)in normotensives.Also,there was still a lack of a correlation between plasma PCSK9 level and SBP and DBP in both hypertensives and normotensives regardless of sex.Moreover,there was a negative correlation between PCSK9 and PP only in female normotensives.Additionally,PCSK9 level was positively associated with LDL-C,apolipoprotein B,apolipoprotein Al and hemoglobin Alc in both groups but high-density lipoprotein cholesterol in normotensives.Conclusions:Our present study demonstrated that PCSK9 level was not associated blood pressure including SBP and DBP in either hypertensions or normotensives,suggesting that the inhibition of PCSK9 could have no effect on BP.In addition,our results exhibited that PCSK9 was not associated independently with IMT.Further study is needed to clarify the relationship between PCSK9 and blood pressure and carotid atherosclerosis.Background and Objective:Proprotein convertase subtilisin/kexin type 9(PCSK9)as a proprotein convertase secreted by liver increases the circulating low-density lipoprotein(LDL)cholesterol as a result of inhibiting LDL receptor.It has been demonstrated that PCSK9 is involved in not only lipid homeostasis but also glucose metabolism.However,it is controversial regarding the relationship between PCSK9 and glucose metabolism.Glycated haemoglobin(HbA1c)is a "gold standard" for monitoring long-term glycemic control and a predictor of lipid metabolism and type 2 diabetes mellitus.Therefore,in the present,we aimed to investigate the association of PCSK9 with HbA1c in patients with T2DM without usage of lipid-lowing drugs.Methods:We consecutively enrolled 805 subjects who were hospitalized in the dyslipidemia center of Fuwai Hospital between October 2012 and Octorber 2014,including 176 patients with type-2 diabetes(T2DM)and 629 non-diabetic patients.The baseline characteristics were collected,biochemical parameters were detected by automatic biochemistry analyzer and serum PCSK9 level was assessed by high-sensitivity,quantitative sandwich enzyme immunoassay.Univariable regression analysis and multiple variable regression analysis were used to examine the associations of PCSK9 with HbA1c.Furthermore,the HbA1c was compared across the tertiles of PCSK9 levels.And also,PCSK9 levels were compared in poorly-controlled(HbA1c≥7.00%)and well-controlled(HbA1c<7.0%)T2DM patients.Results:PCSK9 levels were positively correlated with LDL-C in both T2DM and non-T2DM.Univariable regression analysis revealed a positive association between PCSK9 and HbA1c in T2DM patients(β=0.255,p=0.001)but not in non-diabetic patients(β=0.061,p=0.128).Multiple variable regression analysis exhibited that PCSK9 was independently correlated with HbA1c in T2DM after adjustment for traditional atherosclerotic risk factors(β=0.197,p=0.020).Moreover,HbA1c level was higher in patients with the highest tertile of PCSK9 than that in the lowest tertile(p=0.042).Additionally,higher levels of PCSK9 were found in poorly-controlled group compared to the well-controlled group(p=0.029).Conclusions:Data firstly suggested a positive correlation of PCSK9 levels with HbA1c in T2DM patients but not in non-T2DM patients,indicating a potential role of PCSK9 in type-2 diabetes.Background and Objective:Proprotein convertase subtilisin/kexin type 9(PCSK9)mainly secreted by liver plays a major regulatory role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor(LDLR),thereby increasing circulating LDL cholesterol(LDL-C)levels.Apart from its effect on lipid metabolism,PCSK9 is also associated with glucose homeostasis but the details remain unclear.Glucagon-like peptide-1(GLP-1)is secreted from intestinal L cell and can increase insulin secretion in a glucose-dependent manner and lower blood glucose.GLP-1 not only play a role in glucose regulation but also decreases LDL-C concentration.However,the relationship between GLP-1 and PCSK9 remains unknown.Hence,we aimed to investigate the effect of GLP-1 on PCSK9 expression.Methods:At the cellular level,the expression of PCSK9 protein in HepG2 cells stimulated by liraglutide was examined using Western blot.We divided the mice into 4 groups:db/db mice treated by liralutide(n=12,7-week old),db/db mice treated by saline(n=12,7-week old),wild type mice treated by liralutide(n=8,7-week old)and wild type mice treated by saline(n=8,7-week old).The mice received subcutaneous injection of either liraglutide(200ug/kg)or 0.9%saline of the equal volume twice daily for 7 weeks.Fasting glucose level,food intake and body weight were measured every week.After 7 weeks treatment,the blood was collected for lipid and PCSK9 dectection and the liver was removed from the mice for oil red O staining,immunohistochemical analysis,immunofluorescence test,western bolt and RT-PCR.Results:Liralutide inhibits the expression of PCSK9 protein in HepG2 cells in a time and concentration dependent manner.In the animal experiments,the results were as follows:firstly,food intake and body weight gain were reduced in both wild type and db/db mice treated by liraglutide.The fasting glucose level was reduced in db/db mice treated by liraglutide compared with the saline-treated db/db mice,but there was no significant difference in fasting glucose level between the wild type mice treated by liralutide or salince;secondly,liraglutide decreased the levels of LDL-C,total cholesterol,triglyceride and HDL-C in db/db mice but not in wild type mice;thirdly,the serum PCSK9 level was higher in db/db mice treated by liraglutide[27.00(19.34,35.50)]compared with the db/db mice treated by saline[38.87(29.73,49.80),P=0.021].Nevertheless,no significant difference in serum PCSK9 level was found between the wild type mice treated by liralutide or saline;fourthly,liraglutide reduced hepatocyte steatosis in db/db mice;finnally,liraglutide decreased the hepatic PCSK9 expression in db/db mice but not in wild type mice.Conclusions:Liraglutide inhibited the expression of PCSK9 in HepG2 cells,decreased the hepatic PCSK9 expression in db/db mice but not in wild type mice,and improved hepatic steatosis in db/db mice.