Sortilin drives hypertension by modulating sphingolipid/ceramide homeostasis and by triggering oxidative stress

Abstract

Sortilin is a glycoprotein mainly known for its role as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Its actual contribution to essential hypertension has remained hitherto elusive. Combining top-notch in vivo, ex vivo, and in vitro approaches to clinical investigations, Di Pietro et al. explored the signaling pathway evoked by sortilin in endothelial cells and report on such exploration in this issue of the JCI. The researchers identified circulating sortilin as a biomarker associated with high blood pressure. Mechanistically, they demonstrate that sortilin altered sphingolipid/ceramide homeostasis, initiating a signaling cascade that, from sphingosine-1-phosphate (S1P), leads to the augmented production of reactive oxygen species. Herein, we discuss the main implications of these findings, and we anticipate some of the potential avenues of investigation prompted by this discovery, which could eventually lead to treatments for cardiometabolic disorders.

Figure 1. Main molecular pathways activated by sortilin and the sphingolipid/ceramide signaling cascade in the endothelial cell.

Hypertensive patients display endothelial dysfunction, dysregulation of the sphingolipid/ceramide homeostasis, and elevated oxidative stress. Sortilin levels are linked to endothelial dysfunction and hypertension, and circulating sortilin is proposed as a biomarker associated with high blood pressure. Sortilin, by orchestrating the intracellular trafficking of enzymes implicated in the metabolism of ceramides, signals through the S1P pathway, augmenting ROS production and eventually impairing endothelium-dependent relaxation. Specifically, S1P triggers S1P3-mediated signaling, leading to NOX2 activation via PKCɛ and PYK2. Sortilin activated a precise pathway that is independent of specific eNOS phosphorylation sites, including Ser1177 and Thr494. The phosphorylation sites of eNOS can activate or inhibit the enzyme; the inhibitory sites are Ser114 (phosphorylated by PKCε), Thr494 (phosphorylated by PKCε; actually, the threonine is in position 492 in human eNOS, in position 494 in murine eNOS, and in position 495 in bovine eNOS), Tyr657 (phosphorylated by PYK2); the sites activating eNOS are Ser615 (phosphorylated by AKT and CaMKIV), Ser633 (phosphorylated by PKA, not included in the figure), and Ser1177 (phosphorylated by AKT and CaMKIV). aCDase, acid ceramidase; CaMKIV, Ca²⁺/calmodulin-dependent protein kinase IV; DAG, diacylglycerol; DCS, dihydroceramide synthase (also known as ceramide synthase 3 [CS3]); DES, dihydroceramide desaturase; ER, endoplasmic reticulum; Gq, G protein α subunit q; IP3, inositol 1,4,5-trisphosphate; IP3R, inositol 1,4,5-trisphosphate receptor; IR, insulin receptor; KDHR, 3-ketodihydrosphingosine reductase; NOX2, NADPH oxidase 2; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; SPHK, sphingosine kinase; SPNS2, sphingolipid transporter 2; SPPase, S1P phosphatase; SPT, serine palmitoyltransferase.