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Objective: To investigate the relationship between plasma level of pro-protein convertase subtilisin kexin type9 (PCSK9) and coronary artery calcification (CAC). Methods: A total of 380 consecutive chest pain patients without lipid-lowering therapy were enrolled. All patients received CT scan and coronary artery calcification (CAC) score measurement and were divided into 2 groups: CAC group, n=156 patients with CAC score>0 and Non-CAC group, n=224 patients with CAC score=0. CAC group was further classified in 3 subgroups as CAC score (1-100) subgroup, n=53, CAC score (101-400) subgroup, n=64 and CAC score>400 subgroup, n=39. Clinical data was collected, plasma levels of PCSK9 were measured in all patients and the relationship between PCSK9 and CAC score was investigated. Results: Plasma PCSK9 level in CAC group was higher than Non-CAC group (260.23±69.34) ng/ml vs (205.46±53.21) ng/ml, P<0.001; alone with CAC score increasing, PCSK9 level was elevating accordingly as in CAC score (1-100) subgroup, CAC score (101-400) subgroup and CAC score>400 subgroup, PCSK9 levels were (247.38±72.68) ng/ml, (264.87±57.63) ng/ml and (295.33±69.06) ng/ml respectively, all P<0.05. With adjusted traditional cardiovascular risk factors, multivariate regression analysis confirmed that plasma PCSK9 level was independently related to CAC score (β=0.584, P=0.002). In addition, the optimal cut-off value for PCSK9 predicting CAC was 228.58 ng/ml with sensitivity at 67% and specificity at 71%. Conclusion: Plasma PCSK9 level was related to CAC in chest pain patients without lipid-lowering therapy.
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Objective To investigate the correlation between serum proprotein convertase subtilisin/kexin 9 (PCSK9) level and the severity of angiographic coronary artery disease (CAD) in elderly patients with acute myocardial infarction (AMI) complicated with type 2 diabetes mellitus (T2DM). Methods The patients over the same period were divided into three groups:the elderly patients with AMI and T2DM (observation group, n=46), the elderly non diabetic patients with AMI (positive control group, n=34) and patients with chronic stable coronary heart disease (negative control group, n=33). The serum PCSK9 level was detected by enzyme-linked immunosorbent (ELISA) in three groups. The correlation between serum PCSK9 level and low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (TC), glycosylated hemoglobin (HbA1c), high sensitive C reactive protein (Hs-CRP) and Gensini score were analyzed. Results The levels of PCSK9, HbA1c, Hs-CRP and Gensini score showed a gradually increased tendency in negative control group, positive control group and observation group. Multiple comparison differences between groups were statistically significant (P0.05). Conclusion The serum level of PCSK9 is positive correlated with the severity of CAD, which can be used to determine the severity of coronary artery lesions in elderly patients with AMI complicated with T2DM.
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Objective To investigate the frequency distribution of proprotein convertase subtilisin/kexin 9 (PCSK9) gene I474V polymorphisms and their relationship with patients with ischemic stroke (IS)of Uygur and Han ethnic groups in Xinjiang Uygur Autonomous Region.Methods The I474V polymorphism was identified by polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) in 407 patients with IS(including 219 Hans and 188 Uygurs)and 425 health controls (including 255 Hans and 170 Uygurs),and some specimens were sequenced.Results (1) Between IS group and control group,the genotypes Ⅱ and Ⅳ had no statistically significant differences in the levels of triglycerides (TG),high-density lipoprotein cholesterol (HDL-C) ; Total cholesterol (TC),low-density lipoprotein cholesterol (LDL-C) levels had statistically significant differences; LDL-C levels had also statistically significant differences.Between IS and control groups,TC,LDL,HDL-C levels of genotype Ⅱ showed statistically significant difference.In the IS group,TC,LDL-C levels of Ⅳ genotype were significantly higher than the control group,the difference being statistically significant.(2) There was statistically significant difference in the genotype distribution between IS and control groups (9.5％ (77/814) vs 4.5％ (38/850),x2 =16.09,P =0.000).And the distribution of allele frequency was statistically different (18.9％ (77/407) vs 8.9％ (38/425),x2 =17.38,P =0.000).(3) The differences of I474V loci Ⅳ genotype frequency distribution in Xinjiang Uygurs and Hans were statistically significant (27.7％ (52/188) vs 11.4％ (25/219),x2 =17.40,P =0.000; 12.9％ (22/170) vs 6.3％ (16/255),x2 =5.57,P =0.018) ; So did the Ⅴ allele frenquency distribution (13.8％ (52/376) vs 5.7％ (25/438),x2 =15.58,P =0.000; 6.5％ (22/340) vs 3.1％ (16/510),x2 =10.44,P =0.001).(4) There was statistically significant difference in the genotype distribution and allele frenquency distribution between IS group and control group in the Xinjiang Uygurs (27.7％ (52/188) vs 12.9％ (22/170),x2 =11.79,P =0.001 ; 13.8％ (52/376) vs 6.5％ (22/340),x2 =10.44,P =0.001) ; But there was no statistically significant difference in the Hans.Conclusions Ⅱ and Ⅳ genotypes are dominant in the I474V polymorphism loci of PCSK9 gene.The genotype of PCSK9 gene I474V polymorphism is correlated with increasing serum levels of TC and LDL-C.I474V polymorphism is associated with cerebral IS course in Xinjiang region.There is statistically significant difference in the genotype I474V distribution between Uygur and Han groups.I474V polymorphism has a relationship with the occurrence of IS in Xinjiang Uygurs.Ⅳ may be a susceptible genotype and Ⅴ may be a genetic susceptible allele of the Xinjiang Uygurs.
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Objective To investigate the effects of tumor-necrosis factor α (TNF-α) on the expressions of proprotein convertases (PC) and its relationship with the inhibition of hepatitis B virus (HBV) replication.Methods HepG2.2.15 cells cultured routinely were exposed to 20 μg/L recombinant TNF-α and/or 20 μmol/L PC inhibitor (DEC) for 18 h.Then Followed cells werecollected and cell total RNA and HBV DNA were extracted.PC mRNA and core-associated HBV DNA were measured using real-time polymerase chain reaction (PCR) techniques.Measurement data was compared using t-test.Results When PC mRNA expressions in the blank group was as to 1,the expressions of PC1/3、PC2、furin、PC4 、PC5/6 、PACE4 and PC7/8 mRNA in HepG2.2.15 cells treated with 20μg/L TNF-α treatment for 18 h were all up-regulated,which were 3.3±0.7、79.3±3.3、77.5±1.3、19.2±3.1、1.3±0.1、1.4± 0.2、274.8± 7.1,respectively (all P＜0.05).Treatment of 20 μg/L recombinant TNF-α for 18 h significantly reduced core-associated HBV DNA compared with blank gourp (0.21∶1,t =8.79,P =0.002),while 20 μmol/L DEC significantly up-regulated core-associated HBV DNA (3.84∶ 1,t=7.67,P=0.004).Moreover,core-associated HBV DNA in group of DEC and TNF-α treatment was significantly higher than group of TNF-α treatment (0.31∶0.21,t=10.49,P=0.007).Conclusion Up-regulated PC mRNA expression induced by TNF-α is significantly associated with the inhibition of HBV replication.
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Objective To investigate the correlation between the single nucleotide polymorphisms (SNPs) of rs3811951 at proprotein convertase subtilisin/kexin type 1 (PCSK1) and rs2021785 at PCSK2 gene and the genetic predisposition to newly diagnosed type 2 diabetes (T2DM) in Han population in Chongqing district. Methods A case-control study was performed in Han Chinese subjects with 152 cases of normal control and 227 cases of T2DM patients. Clinical data and blood samples were collected, blood glucose, lipids and other biochemical indexes were determined, and the SNPs of rs3811951 and rs2021785 were genotyped by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results The minor allele frequency of rs2021785 at PCSK2 was significantly lower in T2DM group than in control group (20.04% vs 26.64%, P=0.0335), and carriers of A allele showed a lower risk of suffering T2DM (OR=0.69, 95%CI 0.49-0.97, P=0.0335). The AA genotype frequency of rs2021785 at PCSK2 was significantly lower in T2DM group than in control group (6.6% vs 10.5%, P0.05). Conclusion SNP of rs2021785 at PCSK2 is significantly associated with T2DM in Han population in Chongqing district, however, there is no significant association between SNP of rs3811951 at PCSK1 and T2DM.
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Paired basic amino acid cleaving enzyme 4 (PACE4),a subtilisin-like endoprotease,which is thought to play a significant role in tumor occurrence and development.Its over or low expression may lead to enhanced proliferation and invasion of tumor cells,and even increase the malignant degree.The specific regulation according to the roles of PACF4 expression in different tumors may be helpful for tumor treatment and prognosis improvement.
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As estatinas são produtos farmacêuticos de grande sucesso em todo mundo. Entretanto, muitos pacientes, ou por não as tolerarem adequadamente, ou por necessitarem de taxas mais baixas de LDL-colesterol estabelecidas como metas, poderão ter benefícios clínicos com o emprego de novos medicamentos. Numerosas linhas de pesquisa encontram-se em evolução, avaliando produtos com atuação em diferentes vias moleculares: inibidores de síntese da apolipoproteína B, inibidores da DGAT2, da ACAT2, da MTP, da esqualeno sintase, tireoidemiméticos e inibidores da PCSK9. Espera-se, para futuro próximo, a introdução no mercado desses medicamentos, que poderão auxiliar ainda mais na prevenção primária e secundária da doença aterosclerótica coronária, flagelo deste novo século.
Statins are pharmaceutical products that obtained worldwide success. However, some patients with inadequate tolerability to these medications and the need of achieving lower LDL-cholesterol levels as recommended targets, may receive clinical benefits with the use of new drugs. Many research lines have been in evolution evaluating products that act in different molecular pathways: inhibitors of apoliprotein B synthesis, inhibitors of DGAT2, ACAT2, MTP, squalene synthase, thyromimetics, and inhibitors of PCSK9. It is a hope that the future introduction of many of these products on the market will help furthermore primary and secondary prevention of coronary heart disease, a scourge of this new century.
Subject(s)
Humans , Apolipoproteins B/analysis , Atherosclerosis/complications , Atherosclerosis/mortality , Cholesterol, LDL/analysis , Cardiovascular Diseases/complications , Cardiovascular Diseases/mortality , Thyroid Hormones/analysis , Oligonucleotides, Antisense , Proprotein ConvertasesABSTRACT
AIM:To study the effect of proprotein convertases (PCs) on the transforming growth factor (TGF) ?1-induced inhibition of HBV replication.METHODS:HepG2.2.15 cells cultured regularly were exposed to recombinant TGF?1 at concentration of 2 ?g/L or 5 ?g/L and/or PC inhibitor at concentration of 20 ?mol/L for 18 h.The total RNA and HBV core particle DNA were extracted from these cells,and PC mRNA and core-associated HBV DNA were detected by real-time PCR technique.RESULTS:The mRNA expression levels of 7 PCs in HepG2.2.15 cells were observed with various degrees.Recombinant TGF?1 significantly up-regulated the mRNA expression of all PCs except for the down-regulation of PC5 /6,though PC1 /3 and PC2 were up-regulated most obviously.Furin and PACE4 were the predominant PCs before and after TGF?1 exposure when the basic mRNA expression was taken into account.Further study showed that TGF?1-induced the inhibition of HBV replication was abrogated by PC inhibitor in HepG2.2.15 cells.CONCLUSION:TGF?1-induced the inhibition of HBV replication is mediated by the up-regulation of PCs,which might be of many implications in efficient interferences of TGF?1 on HBV replication.
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Objective:To extract the mung bean trypsin inhibitor(MBTI) from mung bean and to study the inhibitory activity of MBTI against proprotein convertases(PCs).Methods: MBTI was purified to homogeneity by ammonium sulfate precipitation, sequential chromatography of gel filtration,ion exchange,affinity chromatography and HPLC.The high expression strains of 2 PCs,Kexin and Furin,were selected.Kexin and Furin were purified by ammonium sulfate precipitation and gel filtration.The inhibitory activity of MBTI against Kexin and Furin was assayed and the inhibitory constants(Ki) of MBTI against the 2 PCs were calculated by Dixon's plot.Results:The purified MBTI showed a single peak on HPLC and a single band on SDS-PAGE.The inhibitory activity of MBTI against Kexin(Ki= 3.9?10~(-9)mol/L) was stronger than that against Furin.Conclusion: MBTI can inhibit both Kexin and Furin,especially Kexin,and also can be an ideal inhibitor against PCs after further modification.