Angiotensin-Converting Enzyme Gene D/I Polymorphism in Relation to Endothelial Function and Endothelial-Released Factors in Chinese Women.

Yuanyuan Lv,Li Zhao,Wenying Zhao,Ji-Guo Yu,Laikang Yu

doi:10.3389/fphys.2020.00951

Abstract

Many studies have investigated the relationship between angiotensin-converting enzyme (ACE) D/I polymorphism and cardiovascular disease or endothelial dysfunction; however, hardly any of these studies has taken aging or menopause into consideration. Furthermore, despite that many studies have examined the regulatory effects of endothelial-released factors (ERFs) on endothelial function, no study has evaluated the relationship between ERFs and endothelial function with respect to ACE D/I polymorphism and menopause status. To answer these questions, 391 healthy Chinese women over a wide range of ages (22–75 years) were enrolled and divided into pre-menopause group and post-menopause group. After ACE D/I genotype being identified, the women were then classified into either DI/II or DD genotype. Flow-mediated dilatation (FMD) of brachial endothelium and plasma levels of ERFs: nitric oxide (NO), endothelin-1 (ET-1), and angiotensin II (Ang II) were measured. The results showed that frequencies of ACE D/I genotypes were in accordance with the Hardy-Weinberg equilibrium, and the frequency of I allele was higher than D allele. In pre-menopause group, FMD was significantly higher in women of DI/II than DD (P = 0.032), and age-dependent in both genotypes (DD, P = 0.0472; DI/II, P < 0.0001). In post-menopause group, FMD was similar between women of DI/II and DD, and age-dependent only in women of DI/II (P < 0.0001). In pre-menopause group, Ang II level was significantly higher in women of DD than DI/II (P = 0.029), and FMD was significantly correlated with all ERFs in women of DD (NO, P = 0.032; ET-1, P = 0.017; Ang II, P = 0.002), but only with Ang II in women of DI/II (P = 0.026). In post-menopause group, no significant difference was observed in any ERF between women of DI/II and DD, and FMD was only significantly correlated with ET-1 in women of DD (P = 0.010). In summary, FMD in women of DI/II was superior to DD in pre-menopause and more age-dependent than DD in post-menopause, and FMD was closely associated with ERFs. In conclusion, Chinese women of DI/II seem to have lower risk than DD in pre-menopause, but similar risk as DD in post-menopause in developing cardiovascular disease.

Highlights

Endothelium-dependent vasodilation impairment is believed to be the initial factor in the pathogenesis of atherosclerosis, according to the “endothelial damage response theory” (Gimbrone and García-Cardeña, 2016; Ungvari et al, 2018b), and reduction in endothelial function presents a strong correlation with aging, especially after the age of 45 years (Shi et al, 2014; Sepúlveda et al, 2017; Jia et al, 2019) when menopausal transition generally occurs
Comparisons of the data between pre-menopause group and post-menopause group of the same Angiotensin-converting enzyme (ACE) genotype revealed that women of ACE DI/II had significantly higher of both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in postmenopause group than in pre-menopause group (P = 0.012 and P = 0.006, respectively)
Comparisons in mean values of Flow-mediated dilation (FMD) between women of ACE DD and ACE DI/II within pre-menopause group and post-menopause group showed significant difference only in pre-menopause group, where FMD mean value was significantly lower in women of ACE DD than ACE DI/II (P = 0.032)

Summary

Introduction

Endothelium-dependent vasodilation impairment is believed to be the initial factor in the pathogenesis of atherosclerosis, according to the “endothelial damage response theory” (Gimbrone and García-Cardeña, 2016; Ungvari et al, 2018b), and reduction in endothelial function presents a strong correlation with aging, especially after the age of 45 years (Shi et al, 2014; Sepúlveda et al, 2017; Jia et al, 2019) when menopausal transition generally occurs. ACE is a key enzyme of renin-angiotensin system, which together with kallikrein-kinin system is important in maintaining physiological functions of the heart, blood vessels, and kidneys through the regulation of blood pressure, blood flow, homeostasis, and the vasomotor system (Bader, 2010; Masuyer et al, 2012). In the 16th intron of the ACE gene, there is a 287 bp Alu repeat insertion/deletion, and when the ACE allele contains this fragment, it is called “I” (insertion type). If not, it is called “D” (deletion type); ACE has three different genotypes: type II, DI, and DD (Kim et al, 2001)

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