Deletion of soluble epoxide hydrolase suppressed chronic kidney disease-related vascular calcification by restoring Sirtuin 3 expression

Wanbing He,Hui Huang,Jie Chen,Xinhong Zhu,Yang Liu,Jieping Huang,Kun Zhang,Changming Xie

doi:10.1038/s41419-021-04283-6

Abstract

Vascular calcification is common in chronic kidney disease (CKD) and contributes to cardiovascular disease (CVD) without any effective therapies available up to date. The expression of soluble epoxide hydrolase (sEH) is different in patients with and without vascular calcification. The present study investigates the role of sEH as a potential mediator of vascular calcification in CKD. Both Ephx2−/− and wild-type (WT) mice fed with high adenine and phosphate (AP) diet were used to explore the vascular calcification in CKD. Compared with WT, deletion of sEH inhibited vascular calcification induced by AP. sEH deletion also abolished high phosphorus (Pi)-induced phenotypic transition of vascular smooth muscle cells (VSMCs) independent of its epoxyeicosatrienoic acids (EETs) hydrolysis. Further gene expression analysis identified the potential role of Sirtuin 3 (Sirt3) in the sEH-regulated VSMC calcification. Under high Pi treatment, sEH interacted with Sirt3, which might destabilize Sirt3 and accelerate the degradation of Sirt3. Deletion of sEH may preserve the expression of Sirt3, and thus maintain the mitochondrial adenosine triphosphate (ATP) synthesis and morphology, significantly suppressing VSMC calcification. Our data supported that sEH deletion inhibited vascular calcification and indicated a promising target of sEH inhibition in vascular calcification prevention.

Highlights

Vascular calcification is a highly regulated process sharing a similar mechanism with bone formation [1]
A high phosphorus (Pi) level resulting from dysregulated mineral balance in chronic kidney disease (CKD) drives the occurrence of vascular calcification [1]
The Atherosclerosis Risk in Communities (ARIC) study reports that the K55R variant of Ephx2, which results in elevated Soluble epoxide hydrolase (sEH) activity, increases the risk of congenital heart disease [6]

Summary

Introduction

Vascular calcification is a highly regulated process sharing a similar mechanism with bone formation [1]. It is commonly observed in aging and chronic diseases such as chronic kidney disease (CKD) [2]. A high phosphorus (Pi) level resulting from dysregulated mineral balance in CKD drives the occurrence of vascular calcification [1]. Using epoxide hydrolase inhibitors or deletion of Ephx, the encoding gene of sEH, causes the increased level of EETs and shows cardioprotective properties [4]. Clinical studies on different polymorphisms of Ephx show inconsistent association with vascular calcification. The Atherosclerosis Risk in Communities (ARIC) study reports that the K55R variant of Ephx, which results in elevated sEH activity, increases the risk of congenital heart disease [6]

Methods

Results

Conclusion