Association Of ACE2-Ang-(1-7)-Mas Axis With Coronary Heart Disease

Objective The aim of the present study was to investigate the association of circulating levels of angiotensin-converting enzyme 2(ACE2),angiotensin(Ang)-(1-7)and Ang-(1-9)with coronary heart disease(CHD),to investigate the association of the ACE2 gene polymorphisms with CHD,and the association between ACE2 gene polymorphisms and circulating ACE2,Ang-(1-7)and Ang-(1-9)levels in patients with CHD.The relationship between ACE2-Ang-(1-7)-Mas axis and CHD was explored from the perspective of circulation and genetics,and our findings would provide potential endogenous biomarkers and intervention targets for prevention and treatment of CHD.Methods 275 patients who were referred to coronary angiography(CAG)for the evaluation of suspected CHD were enrolled.CHD was defined as significant coronary stenosis(?50%)in at least one major coronary artery following the World Health Organization(WHO)criteria.According to this,all subjects were divided into two groups:CHD group and non-CHD group.The number of stenotic coronary vessels and the SYNTAX score of each coronary lesion were evaluated by two experienced cardiologists by using the online Syntax score calculator.The general clinical data and Laboratory data of each study object were recorded.Circulating ACE2,Ang-(1-7)and Ang-(1-9)levels were detected by enzyme-linked immunosorbent assay(ELISA).We selected four tag single nucleotide polymorphisms(SNPs)(rs2106809,rs2074192,rs4646155 and rs4646171)for genetic association study,and identified the polymorphisms of ACE2 gene by using mass spectrometric analysis.All analyses were performed using IBM SPSS statistical software(version 25.0;IBM Corp,Armonk,NY).A standard one-way analysis of variance(ANOVA)test was used for comparisons of circulating levels of ACE2,Ang-(1-7)and Ang-(1-9)levels,the correlation of between circulating levels of ACE2 and SYNTAX score were analyzed by spearman correlation analysis.The comparison of genotype and allele frequency distribution of ACE2 gene between CHD group and non-CHD group were analyzed by chi-square test.Logistic regression analysis was used to determine the independent risk factor for CHD.ResultsI Males had significantly higher circulating ACE2,Ang-(1-7)levels,while lower Ang-(1-9)levels than females.2 The circulating ACE2 levels were increased in female CHD patients when compared to non-CHD patients(P=0.009),while Ang-(1-7)and Ang-(1-9)levels had no significant differences between two groups.There were also no significant differences of circulating ACE2,Ang-(1-7)and Ang-(1-9)levels between male patients with and without CHD.3 In females,logistic regression analysis showed that those in the highest quartile had an OR of 4.33(95%CI 1.20-15.61)for the CHD(P for trend = 0.025 when compared with the people in the lowest ACE2 quartile,the OR was 5.94(95%CI 1.08-32.51)for the third ACE2 quartile and 9.58(95%CI 1.61-56.95)for the highest ACE2 quartile after adjusting for potential confounders(P for trend = 0.022).4 In females,circulating ACE2 levels were increased with the increase of diseased coronary arteries,significant difference was found between the multi-vessel lesions group and the non-CHD group(P=0.009),but not in other groups.Circulating ACE2 levels had no correlation with the complexity of atherosclerosis assessed by SYNTAX score(P = 0.159).5 In females,for rs2106809,the genotype frequency of CT+TT in the CHD group was significantly higher than the non-CHD group(P=0.027).In males,there ware no significant differences in allele frequencies between two groups.6 In females,carriers of rs2106809 TT+CT genotype had an increased risk of CHD in logistic regression analysis(P=0.012),compared with CC genotype,the OR value of TT+CT genotype was 14.611(95%C1=1.810-117.983).7 The serum Ang-(1-7)levels were significantly greater in female patients carrying the rs2074192 TT genotype compared with those carrying the CT+CC genotype(P=0.037),whereas the serum ACE2,Ang-(1-7)and Ang-(1-9)levels were comparable among genotypes in male patients.Conclusions1 In females,circulating ACE2 levels significantly increased in CHD group when compare with non-CHD group.After adjusting for potential confounders,circulating ACE2 levels was independently associated with CHD in women,the risk of CHD was increased in upper quartile groups of ACE2.2 Carriers of the rs2106809 TT+CT genotype were at higher risk of CHD in female subjects,an association was detected with CHD for SNP rs2106809 in dominant model after adjusting for potential confounders,the TT+CT genotype of rs2106809 may be an independent risk factor for CHD in female patients.3 There was a genetic association between circulating Ang-(1-7)levels and SNP rs2074192 in recessive model in female patients with CHD.4 No correlation was found between ACE2-Ang-(1-7)-Mas axis and CHD in male subjects.