Effects Of IRS-1G972R Polymorphisim On Human Endothelial Function And Inflammation And Study On Their Mechanism

Objective:To investigate the interrelationship between IRS-1gene Gly972Arg polymorphism and primary hypertension,insulin resistance and endothelial dysfunction in Han people from Changsha,Zhuzhou and Xiangtan district.HuNan province.Methods:184hypertensive patients,178insulin-resistant patients,145hypertensive and insulin-resistant patients and520healthy controll people were recruited from Changsha,Zhuzhou and Xiangtan district.HuNan province. BMI, WHR, BP,BS; blood fat, hepatic and renal function were measured,insulin resistant state were assessed by OGTT. FMD were determined through HP Sonos5500color ultrasound system, IRS-1gene Gly972Arg polymorphism were detected by PCR-RFLP.Results:IRS-1gene Gly972Arg polymorphism coincide with Hardy-Weinberg equilibrium law. G/A allelic frequency:9heterogeneic carriers were detected from329hypertensive patients(2.7%),10were detected from701normotensive patients(1.4%);7were found in326insulin-resistant patients(2.1%),12were found in704subjects without insulin resistance(1.7%).Statistical difference can neither be found between hypertensive group and normotensive group nor between insulin-reisistant group and subjects without insulin resistance. Logistic regression analysis demonstrate that only hypertensive degree serves as independent risk factor of endothelial dysfunction (OR=1.983,95%CI1.215-2.573, P=0.028). No statistical relationship had been found between endothelial dysfunction and IRS-1Gly972Arg polymorphism,insulin resistance,nor the interaction between IRS-1Gly972Arg polymorphism&insulin resistance.Conclusion:Hypertensive degree serves as independent risk factor of endothelial dysfunction. No statistical relationship had been found between endothelial dysfunction and IRS-1Gly972Arg polymorphism,insulin resistance,nor the interaction between IRS-1Gly972Arg polymorphism&insulin resistance. Objective:To investigate a potential interrelationship between HBP,IRS-1G972R polymorphism,insulin-resistance and even FMD in vivo.Methods:a eight cohorts of10Gly/Gly carriers without HBP or IR,10Gly/Gly carriers with HBP but without insulin resistance,10Gly/Gly carriers with insulin resistance but without HBP,10Gly/Gly carriers with HBP and insulin resistance,10heterozygous carriers without HBP or insulin resistance,10heterozygous carriers with HBP but without insulin resistance,10heterozygous carriers with insulin resistance but without HBP,10heterozygous carriers with HBP and insulin resistance were enrolled respectively. The study population were Han people from Hunan Province,China.IRS-1polymorphism was detected by PCR.Endothelium-dependent vasodilution in terms of FMD were assessed by noninvasive color ultrasound system. ET-1,eNos and IL-8, ICAM-1were determined by enzyme linked immunosorbent assay,while the expression of mononuclearcell CXCR2mRNA were measured by Real-time PCR.Results:Allelic mutation frequency of G972R IRS-1allele were11.1%.No statistical difference were found between IRS-1G972R polymorphism and endothelial dysfunction. Statistical interrelationship lies between endothelial dysfunction and hypertension or plasma ET-1/eNOS level.However,the plasma ET-1/eNOS level of G972R IRS-1variants is statistically higher than that of Gly/Gly carriers,as detected in hypertensive subjects. Plasma IL-8and ICAM-1,as well as PBMC CXCR2mRNA elevated in G972R IRS-1variants compared with Gly/Gly carriers,as detected in insulin-resistant subjects.Conclusion:Through inflammation as well as interaction with HBP, IRS-1G972R polymorphism contribute to impaired FMD, indirectly, and hence cardiovascular disease. OBJECTIVE:To investigate the effects of IRS-1Gly972Arg polymorphism on hypertensive or insulin-resistant subjects treated by captopril or rosiglitazone.Methods:20hypertensive patients,20insulin-resistant patients,20hypertensive and insulin-resistant group and20healthy controll subjects were enrolled randomly as4groups.Each group was subdivided according to G/A genotype.40hypertensive subjects had25mg captopril daily for oral use for1month, the alleosis of plasma of ET-1/eNOS between pre-and post-captopril treatment were analyzed bystatistics.40insulin-resistant subjects had4mg rosiglitazone daily for oral use for2month, the change of PBMC CXCR2mRNA between pre-and post-rosiglitazone treatmentwere also compared through covariance analysis.Results:ET-1/eNOS level decreased after1month of captopril treatment,but no statistical difference was made in the effects of captopril on plasmaET-1/eNOs level,as demonstrated by covariance analysis.Also, covariance analysis showed that insulin resistance and allele had no statistical influence on effects of captopril on FMD elevation. PBMC CXCR2mRNA level declined after2months of rosiglitazone adminstration,but no statistical difference was made in the effect of rosiglitazone on PBMC CXCR2mRNA expression; In addition, covariance analysis revealled that hypertension and allele had no statistical contribution on effects of rosiglitazone on PBMC CXCR2mRNA degression.Conclusion:Captopril adminstration could decrease plasma ET-1/eNOs level of hypertensive subjects and improve endothelial function;Insulin resistance and IRS-1Gly972Arg polymorphism had no influence on the effect of captopril on depressing plasmaET-1/eNOs level. Rosiglitazone adminstration may downregulate PBMC CXCR2mRNA in insulin-resistant subjects,but neither hypertension nor IRS-1Gly972Arg allele showed statistical contribution on the effects of rosiglitazone on PBMC CXCR2mRNA degression.