Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging

Sunao Shimizu,Masayuki Yamamoto,Hirofumi Tomita,Hiroyuki Suganuma,Michiko Tsushima,Hiromi Yamazaki,Eigo Shimizu,Ken Itoh,Junsei Mimura,Shigeyuki Nakaji,Seiya Imoto,Takanori Hasegawa,Yusuke Ushida,Shuya Kasai,Hiroyuki Itabe

doi:10.1371/journal.pone.0236834

Abstract

Pulse wave velocity (PWV), an indicator of vascular stiffness, increases with age and is increasingly recognized as an independent risk factor for cardiovascular disease (CVD). Although many mechanical and chemical factors underlie the stiffness of the elastic artery, genetic risk factors related to age-dependent increases in PWV in apparently healthy people are largely unknown. The transcription factor nuclear factor E2 (NF-E2)-related factor 2 (Nrf2), which is activated by unidirectional vascular pulsatile shear stress or oxidative stress, regulates vascular redox homeostasis. Previous reports have shown that a SNP in the NRF2 gene regulatory region (-617C>A; hereafter called SNP-617) affects NRF2 gene expression such that the minor A allele confers lower gene expression compared to the C allele, and it is associated with various diseases, including CVD. We aimed to investigate whether SNP-617 affects vascular stiffness with aging in apparently healthy people. Analyzing wide-ranging data obtained from a public health survey performed in Japan, we evaluated whether SNP-617 affected brachial-ankle PWV (baPWV) in never-smoking healthy subjects (n = 642). We also evaluated the effects of SNP-617 on other cardiovascular and blood test measurements. We have shown that not only AA carriers (n = 55) but also CA carriers (n = 247) show arterial stiffness compared to CC carriers (n = 340). Furthermore, SNP-617 also affected blood pressure indexes such as systolic blood pressure and mean arterial pressure but not the ankle brachial pressure index, an indicator of atherosclerosis. Multivariate analysis showed that SNP-617 accelerates the incremental ratio of baPWV with age. This study is the first to show that SNP-617 affects the age-dependent increase in vascular stiffness. Our results indicate that low NRF2 activity induces premature vascular aging and could be targeted for the prevention of cardiovascular diseases associated with aging.

Highlights

Cardiovascular disease (CVD) is a major cause of death worldwide
Analyzing wide-ranging data obtained from a public health survey performed in Japan, we evaluated whether SNP−617 affected brachial-ankle Pulse wave velocity (PWV) in never-smoking healthy subjects (n = 642)
We have shown that AA carriers (n = 55) and CA carriers (n = 247) show arterial stiffness compared to CC carriers (n = 340)

Summary

Introduction

Cardiovascular disease (CVD) is a major cause of death worldwide. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) reported that CVD killed 17.8 million people worldwide in 2017, corresponding to 31% of all deaths [1]. Alteration of blood vessels with aging, which manifests as vascular dilation, thickening of intima and media (IM), endothelial dysfunction or arterial stiffening, has been suggested to contribute to the increased risk of CVD due to aging [4, 5]. These factors could appear in the absence of overt clinical CVD during aging and are interrelated, for example, such that the age-associated increase in IM thickening is associated with an increase in vessel stiffness [6]. Arteriosclerosis, which means arterial stiffness, is generally due to the degeneration of the media of vessels Both conditions are the major risk factors for CVD and increase with age [4]. Many mechanical and chemical factors are known to contribute to the stiffness of the conduit artery, the underlying factors related to the age-dependent increase in PWV, especially the genetic factors, are largely unknown [7]

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