# The phosphatase activity of soluble epoxide hydrolase regulates vascular calcification through the metabolism of pyrophosphate anions

## TL;DR

This study shows that the phosphatase activity of an enzyme called sEH helps control vascular calcification by affecting pyrophosphate levels, which could help prevent heart issues in kidney disease.

## Contribution

The novel finding is that sEH's phosphatase activity regulates vascular calcification via pyrophosphate metabolism, particularly in the endothelium.

## Key findings

- Pharmacological and genetic inhibition of sEH-P reduced calcium deposition in rat aortic rings under high-phosphate conditions.
- Inhibiting sEH-P increased pyrophosphate levels and reduced calcification in aortic rings and in a model of chronic kidney disease.
- The anticalcifying effect of sEH-P inhibition was endothelium-dependent and not mediated by endothelial NO release.

## Abstract

While the hydrolase activity of soluble epoxide hydrolase (sEH) reduces vascular calcification, it is not known whether the phosphatase activity of sEH (sEH-P) is also involved. Pharmacological and genetic inhibition of sEH-P reduced the increased calcium deposition in rat aortic rings cultured under high-phosphate conditions. This was associated with decreased mRNA expression of the osteochondrogenic markers Msx2 and Sox9. Deendothelialization of the aortic rings abolished this anticalcifying effect, while the calcification of human aortic smooth muscle cells was unaffected by sEH-P inhibition, suggesting a predominant role of the endothelium. Endothelial NO release did not appear to contribute, but an increased level of the calcification inhibitor pyrophosphate anions (PPi) was observed in the culture supernatant of aortic rings when sEH-P was inhibited. In vitro experiments demonstrated that PPi is a substrate of sEH-P, and that inhibiting sEH-P prevented the high-phosphate induced decrease of PPi in human aortic endothelial cells. Furthermore, the aortic calcification related to chronic kidney disease induced by subtotal nephrectomy was reduced in sEH-P-deficient rats compared to wild-type rats. This was associated with an improvement in flow-induced isolated mesenteric artery dilatation and a reduction of cardiac hypertrophy and fibrosis. Vascular calcification is regulated by sEH-P through the metabolism of endothelial PPi. The prevention of vascular calcification, together with the reduction in vascular dysfunction and cardiac remodeling, suggests that inhibiting sEH-P may help to prevent the cardiovascular complications associated with chronic kidney disease.