Sortilin and hypertension

Abstract

Purpose of review

The current review aims to present the latest scientific updates on the role of Sortilin in the pathophysiology of hypertension.

Recent findings

The main focus of this systematic overview is on the functional contribution of Sortilin to the pathogenesis of hypertension. Sortilin is a glycoprotein mostly known for its actions as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Emerging evidence indicates that Sortilin is associated with pathological conditions, including inflammation, arteriosclerosis, dyslipidemia, insulin resistance, and vascular calcification. Most recently, Sortilin has been shown to finely control endothelial function and to drive hypertension by modulating sphingolipid/ceramide homeostasis and by triggering oxidative stress.

Summary

The latest findings linking Sortilin and hypertension that are herein discussed can inspire novel areas of research which could eventually lead to the discovery of new therapeutic strategies in cardiovascular medicine.

INTRODUCTION

Hypertension is one of the leading causes of death worldwide, and in the last decade a higher incidence has been documented, especially in the adult population. In general, hypertension does not cause any peculiar symptom, but in the long run it becomes a serious risk factor for other major conditions including stroke, coronary heart disease, heart failure, loss of vision, kidney disease, and dementia [1,2].

Hypertension is a complex polygenic disease, in which several genes, or a combination of these, can affect blood pressure [3-5]. To date, more than 25 rare mutations and 120 individual polymorphisms contributing to blood pressure have been recognized [3,6]. Moreover, there are several risk factors that can affect blood pressure, including excessive alcohol consumption, reduced physical activity and increased body mass index, and a diet with excessive sodium intake and/or insufficient intake of potassium [5,7,8]. All these factors alone or in combination cover a large percentage of triggers inducing hypertension.

One of the issues with hypertension is that being a highly heterogeneous disorder, the association of most biomarkers with the risk of hypertension has often been modest, thus being not easily applicable to a proper clinical use [9-17]; therefore, new research strategies are being developed, shifting the attention to other potential biomarkers, which may be soon become novel therapeutic targets. Sortilin represents one of the best examples in this sense.

SORTILIN

Sortilin is a single-pass type 1 transmembrane glycoprotein of approximately 95 kDa encoded by the SORT1 gene (also known as Glycoprotein 95, Gp95, or Neurotensin Receptor 3, NTR3) located on chromosome 1 in humans [18]. Sortilin belongs to the family of vacuolar protein domain receptors 10 (VPS10P), which includes both the Sortilin-related receptor 1 (SORL1) and the Sortilin Related VPS10 Domain Containing Receptor 1–3 (sorCS1–3).

Sortilin consists of a short cytoplasmic tail, a single transmembrane helix, and a large extracellular domain VPS10P. The protein acts as a receptor, co-receptor, and trafficking molecule [19,20^■■,21,22,23^■■].

Sortilin is synthesized as a precursor that includes in its luminal N-terminus a 44-residue-long pro-peptide, called Spadin or Sort-pro [24], which plays a fundamental role in facilitating transport of the pro-receptor through the biosynthetic pathway, until it is cleaved off in the trans-Golgi network by protein convertases [25,26]. In addition to being localized in intracellular compartments, including endoplasmic reticulum and Golgi, Sortilin is also expressed at the cell surface where it acts as an endocytotic receptor for various extracellular ligands. Sortilin is cleaved around the base of its luminal side by the Ca²⁺-regulated transmembrane sheddase ADAM10 (A Disintegrin And Metalloproteinase Domain-Containing Protein 10) [27], and the ectodomain is released as a soluble form into the extracellular space.

At the cellular level, Sortilin is involved in the intracellular transport between endoplasmic reticulum (ER), Golgi apparatus, lysosomes, and plasma membrane, regulating multiple biological processes including glucose and lipid metabolism, the trafficking of extracellular vesicles, as well as cell development and cell death [22,28,29]. Sortilin binds a variety of both circulating and transmembrane targets including cytokines, enzymes, peptides, and growth factors [24,25]. It is abundant in the central nervous system; in fact it was initially identified in the brain tissue and has been extensively studied in the pathobiology of neurological disorders [30-33]. Subsequently, Sortilin has been associated with other pathological conditions, including inflammation, arteriosclerosis, dyslipidemia, insulin resistance, vascular calcification, immune disorders, and cancer [23^■■,34-38].

SORTILIN AND HYPERTENSION

In the last few years Sortilin has become the topic of a number of scientific studies, embodying a leading role in cardiovascular and metabolic diseases, shaping its potential functional contribution both as a reliable biomarker and as a potential therapeutic target.

Circulating Sortilin levels have been found to be associated with a higher risk of arteriosclerosis, major adverse cardiac and cerebrovascular events (MACCE), coronary heart disease, and peripheral arterial disease (PAD) [39,40,41,42^■,43-50].

Sortilin has recently been proven to have a direct role in vascular function, specifically promoting endothelial dysfunction and hypertension [18]. Specifically, in a recent study, Di Pietro et al. [51^■■] explored the role of Sortilin in hypertension. Experimental assays carried out in mice revealed that chronic and acute administration of Sortilin caused an increase in blood pressure.

Sortilin alters the sphingolipid/ceramide homeostasis [18], initiating a signaling cascade (Fig. 1) that, from sphingosine-1-phosphate (S1P) leads to the augmented generation of reactive oxygen species (ROS) through the activation of the NADPH oxidase 2 (NOX2) isoform. Indeed, in mice without S1P lysosphingolipid receptor 3 (S1P3) or gp91phox/NOX2, Sortilin did not induce hypertension or vascular dysfunction (Fig. 2a), suggesting that these pathways are implied in the pathobiology of Sortilin-induced high blood pressure. In addition, using a pharmacological inhibitor (i.e. S1P3 TY52156), only an hour after the administration of Sortilin, it was possible to avoid the harmful effect of Sortilin and blood pressure in mice was lowered to normal values [51^■■].

FIGURE 1.

Main signaling pathways mediated by Sortilin in the endothelial cell. aCDase, acid ceramidase; aSMase, acid sphingomyelinase; DAG, diacylglycerol; DCS, dihydroceramide synthase; DES, dihydroceramide desaturase; ER, endoplasmic reticulum; G_q, subunit q of G protein alpha; KDHR, 3-ketodihydrosphingosine reductase; NOX2, NADPH oxidase 2; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; PKC_ε, protein kinase C epsilon; PLC, phospholipase C; PYK2, protein tyrosine kinase 2 beta; ROS, reactive oxygen species; S1P, sphingosine 1 phosphate; S1PR3, type 3 sphingosine 1 phosphate receptor; SMase, sphingomyelinase; SPHK, sphingosine kinase; SPNS2, sphingolipid transporter 2; SPPase, S1P phosphatase; SPT, serine palmitoyltransferase.

FIGURE 2.

Preclinical and clinical investigations showing that Sortilin drives arterial hypertension. (a) Sortilin induces hypertension through a mechanism that involves sphingosine-1-phosphate (S1P) lysosphingolipid receptor 3 and/or gp91^phox/NOX2. (b) Circulating Sortilin levels are greater in hypertensive patients with noncontrolled hypertension and correlate with S1P levels.

Strikingly, in experimental studies conducted in humans, circulating Sortilin levels were shown to be higher in hypertensive subjects with impaired endothelial function than in normotensive subjects [51^■■]. Of note, these findings have been later confirmed by an independent investigation [52], which has shown that elevated Sortilin levels in the plasma are significantly associated with an increased risk of essential hypertension and subclinical carotid atherosclerosis in hypertensive patients (Fig. 2b).

As mentioned above, Sortilin has been associated with the presence of PAD, and hypertension is known to be one of the main risk factors for the development and progression of this disease [53]. The findings obtained by Di Pietro and coworkers were confirmed in hypertensive individuals with no previous symptoms or diagnosis of PAD, to rule out a possible influence of this comorbidity, confirming that Sortilin is involved in the pathogenesis of hypertension independently of other associated disorders.

In addition, hypertension is strongly connected with oxidative stress and endothelial dysfunction [18,54]. In fact, Sortilin has been shown to induce an over-production of ROS through the activation of NOX2 and to trigger endothelial dysfunction in murine mesenteric arteries [18].

These results support the theory that the activation of the S1P/NOX2 signaling axis induced by Sortilin and the subsequent impairment of endothelial-dependent dilation are involved in the increased blood pressure evoked by Sortilin.

Sortilin has been also linked to insulin resistance in type 2 diabetes mellitus and dyslipidemia, an association that has been suggested to be attributable to an altered hepatic metabolism of apolipoprotein B-100 (apoB-100) [55,56]. Genome-wide association studies have identified a locus on 1p13 as a risk locus for dyslipidemia and myocardial infarction, and a common noncoding polymorphism at the 1p13 locus, rs12740374, has been shown to alter the expression of the SORT1 gene [57^■]. Actually, several single nucleotide polymorphisms (SNPs), that are coupled to an increased hepatic-specific SORT1 expression have been associated with reduced levels of low-density lipoprotein cholesterol (LDL-C) and apoB-100 [58,59]. A recent report demonstrated that these SORT1 SNPs were more protective against the risk of cardiovascular disease in diabetic patients compared to subjects without diabetes [60]. According to the latest studies, this protection could be attributable to a decrease in very-low-density lipoprotein (VLDL) production leading to reduced apoB containing lipoproteins in carriers of the SORT1 variants [61^■]. Furthermore, Sortilin augments secretion of PCSK9 (proprotein convertase subtilisin/kexin type 9 serine protease), which binds the LDL receptor resulting in its endocytosis [62], thereby increasing the risk of atherosclerosis [55,63,64].

Sortilin is also functionally implied in the regulation of vascular calcification. Indeed, it has been shown to be upregulated during osteoblastic differentiation of mesenchymal stem cells and to promote extracellular matrix mineralization [65] and high circulating Sortilin levels have been associated with carotid calcification and severe carotid plaque score [66]. In a series of papers, Claudia Goettsch et al. [20^■■,39,67] have elegantly demonstrated the mechanistic role of smooth muscle cell (SMC)-derived Sortilin in promoting vascular calcification mainly via its trafficking function of tissue non-specific alkaline phosphatase (TNAP) to extracellular vesicles triggering a high mineralization competence in the extracellular milieu; intriguingly, the injection of an adeno-associated virus encoding for PCSK9 to Sortilin-deficient mice led to a significantly reduced aortic calcification (by 46.3%) compared to littermate controls. Posttranslational modifications of Sortilin, including its carbamylation [42^■] and its phosphorylation have been also associated with the calcification process [20^■■].

CONCLUSION

Hypertension is a major widespread problem worldwide; moreover, in recent years its incidence has increased, and it is not excluded that there will be a further increase in the next decade [68]. Although today several pharmaceutical strategies are available, the percentage of successful treatment and control of hypertension is still considerably low, and therefore continues to be a nontrivial problem for public health. In addition, hypertension generally has no specific symptoms other than those attributable to its complications, and it is precisely for this reason that it is often called ‘silent killer’, explaining why finding a dependable way to foresee its actual manifestation, as for example a biomarker, is certainly very important for prevention. Sortilin therefore plays a very important role for this pathological condition and since high circulating levels of Sortilin have been detected in hypertensive patients, this protein could act as a powerful biomarker for the clinical management of hypertension.

Since Sortilin contributes to the risk of hypertension and in general to an increased cardiovascular risk (Fig. 3), it could also be exploited as a potential therapeutic target. It is noteworthy to emphasize that a hypothetical therapy targeting Sortilin may have negative effects on the nervous system, as Sortilin is essential for a proper neuronal activity, inasmuch as it controls protein traffic and the release of neurotrophin, and also affects the signaling pathways governing cell survival and death via p75NTR [69^■]. On the other hand, some studies have identified Sortilin as a risk factor for neurogenerative diseases, such as Alzheimer’s [70]. Of course, additional studies will be needed to better understand the complex biology of Sortilin in the sorting and signaling of proteins.

FIGURE 3.

Impact of Sortilin on cardiovascular risk. Sortilin influences cardiovascular risk acting on several organs and through different pathways.

There are still many limitations regarding the implications of this protein in hypertension and further multicenter and prospective follow-up studies will be needed; notwithstanding, in the future Sortilin could play a decisive role in fighting hypertension and placing new clinical perspectives for the development of new successful therapeutic approaches.

KEY POINTS.

• Sortilin is a transmembrane glycoprotein mainly involved in the intracellular transport between the Golgi apparatus, the lysosomes, and the plasma membrane.

• Circulating levels of Sortilin have been associated with a higher risk of major adverse cardiac and cerebrovascular events.

• Sortilin has recently been shown to play an essential role in the control of vascular function, promoting endothelial dysfunction and hypertension.

• In endothelial cells, Sortilin alters the sphingolipid/ceramide homeostasis, initiating a signaling cascade that from sphingosine-1-phosphate leads to increased oxidative stress.