Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Goettsch, Claudia; Iwata, Hiroshi; Hutcheson, Joshua D.; O’Donnell, Christopher J.; Chapurlat, Roland; Cook, Nancy R.; Aikawa, Masanori; Szulc, Paweł; Aïkawa, Elena

doi:10.1161/atvbaha.116.308932

Cited by 46 publications

(48 citation statements)

References 36 publications

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“…Our findings of dimerized soluble sortilin have important implications in a clinical setting because serum sortilin can act as a biomarker for cardiovascular and neurologic diseases ( 31 – 33 ). Therefore, it is important to clarify the differences between monomers and dimers of soluble sortilin and the monomer/dimer ratio in serum for these diseases.…”

Section: Discussionmentioning

confidence: 85%

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Dimerization of sortilin regulates its trafficking to extracellular vesicles

Itoh

Muramatsu

Aikawa

et al. 2018

Journal of Biological Chemistry

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Extracellular vesicles (EVs) play a critical role in intercellular communication by transferring microRNAs, lipids, and proteins to neighboring cells. Sortilin, a sorting receptor that directs target proteins to the secretory or endocytic compartments of cells, is found in both EVs and cells. In many human diseases, including cancer and cardiovascular disorders, sortilin expression levels are atypically high. To elucidate the relationship between cardiovascular disease, particularly vascular calcification, and sortilin expression levels, we explored the trafficking of sortilin in both the intracellular and extracellular milieu. We previously demonstrated that sortilin promotes vascular calcification via its trafficking of tissue-nonspecific alkaline phosphatase to EVs. Although recent reports have noted that sortilin is regulated by multiple post-translational modifications, the precise mechanisms of sortilin trafficking still need to be determined. Here, we show that sortilin forms homodimers with an intermolecular disulfide bond at the cysteine 783 (Cys783) residue, and because Cys783 can be palmitoylated, it could be shared via palmitoylation and an intermolecular disulfide bond. Formation of this intermolecular disulfide bond leads to trafficking of sortilin to EVs by preventing palmitoylation, which further promotes sortilin trafficking to the Golgi apparatus. Moreover, we found that sortilin-derived propeptide decreased sortilin homodimers within EVs. In conclusion, sortilin is transported to EVs via the formation of homodimers with an intermolecular disulfide bond, which is endogenously regulated by its own propeptide. Therefore, we propose that inhibiting dimerization of sortilin acts as a new therapeutic strategy for the treatment of EV-associated diseases, including vascular calcification and cancer.

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Section: Discussionmentioning

confidence: 85%

“…Previous studies reported that serum sortilin levels are associated with cardiovascular risk, such as aortic calcification ( 31 ) and atherothrombosis ( 32 ), as well as depression ( 33 ). Soluble sortilin can also activate survival pathways in cancer cells ( 6 , 34 ).…”

Section: Resultsmentioning

confidence: 99%

Dimerization of sortilin regulates its trafficking to extracellular vesicles

Itoh

Muramatsu

Aikawa

et al. 2018

Journal of Biological Chemistry

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“…Sortilin has been previously associated with cardiovascular disease, and metabolic and adipose tissue functions 13 – 16 , 18 – 23 , 37 ; however, the connection of Sortilin between atherosclerosis and obesity, including its mechanistic role has not been established. The nuclear receptor, LXR reduces atherosclerotic lesion when activated in several models, but can also induce hepatic steatosis 38 , 39 .…”

Section: Discussionmentioning

confidence: 99%

“…Sortilin has been associated with atherosclerosis, very-low density lipoprotein secretion, macrophage LDL uptake and foam cell formation, inflammatory cytokine secretion, and hepatic steatosis 17 – 21 . Additionally, we recently established a mechanistic role of Sortilin in the loading of extracellular vesicles contributing to cardiovascular calcification 22 , along with associating elevated serum Sortilin to aortic calcification and cardiovascular risk 23 .…”

Section: Introductionmentioning

confidence: 99%

Transcriptional control of intestinal cholesterol absorption, adipose energy expenditure and lipid handling by Sortilin

Hagita

Rogers

Pham

et al. 2018

Sci Rep

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The sorting receptor Sortilin functions in the regulation of glucose and lipid metabolism. Dysfunctional lipid uptake, storage, and metabolism contribute to several major human diseases including atherosclerosis and obesity. Sortilin associates with cardiovascular disease; however, the role of Sortilin in adipose tissue and lipid metabolism remains unclear. Here we show that in the low-density lipoprotein receptor-deficient (Ldlr−/−) atherosclerosis model, Sortilin deficiency (Sort1−/−) in female mice suppresses Niemann-Pick type C1-Like 1 (Npc1l1) mRNA levels, reduces body and white adipose tissue weight, and improves brown adipose tissue function partially via transcriptional downregulation of Krüppel-like factor 4 and Liver X receptor. Female Ldlr−/−Sort1−/− mice on a high-fat/cholesterol diet had elevated plasma Fibroblast growth factor 21 and Adiponectin, an adipokine that when reduced is associated with obesity and cardiovascular disease-related factors. Additionally, Sort1 deficiency suppressed cholesterol absorption in both female mice ex vivo intestinal tissue and human colon Caco-2 cells in a similar manner to treatment with the NPC1L1 inhibitor ezetimibe. Together our findings support a novel role of Sortilin in energy regulation and lipid homeostasis in female mice, which may be a potential therapeutic target for obesity and cardiovascular disease.

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“…15 Therefore, it is feasible to speculate that the serum sortilin level may interact with inflammatory response and be related to CHD susceptibility. Additionally, clinical studies identified sortilin as a risk factor for cardiovascular disease, 16 and SORL1 is also considered to contribute to the development of atherogenesis. 17 However, the mechanism is not entirely clear.…”

Section: Introductionmentioning

confidence: 99%

<p>The Association Between Sortilin and Inflammation in Patients with Coronary Heart Disease</p>

Han¹,

Wei²,

Zhang³

et al. 2020

JIR

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Purpose: Inflammation is a key contributor to coronary heart disease (CHD). Sortilin is a sorting receptor and has been identified as a critical regulator of inflammatory response. Therefore, our study aimed to determine the link between circulating sortilin levels, proinflammatory cytokine levels, and the occurrence of CHD.Patients and Methods: Our study included 227 CHD patients and 101 matched healthy individuals. Circulating serum levels of sortilin and proinflammatory cytokines, including IL-1β, IL-6 and TNF-α, were assessed by a double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA). Linear regression and correlation analyses were used to estimate the associations between sortilin and proinflammatory cytokines. Moreover, six singlenucleotide polymorphisms (SNPs) spanning the sortilin and SORL1 genes were genotyped. Results: Elevated levels of sortilin (P=0.027) and proinflammatory cytokines IL-1β (P=0.013), IL-6 (P=0.000) and TNF-α (P=0.010) were observed in CHD patients compared to those in healthy controls. Furthermore, sortilin levels were significantly positively correlated with IL-1β (r=0.252, P=0.0001), IL-6 (r=0.250, P=0.0001) and TNF-α (r=0.180, P=0.0064) levels. Notably, sortilin polymorphisms were revealed to be associated with the occurrence of CHD and varying sortilin levels. Subjects with the rs599839 AA risk genotype for CHD had significantly higher sortilin levels than those with the GG and GA genotypes (P=0.000); the same tendency was also observed in the levels of the proinflammatory cytokines IL-1β (P=0.003) and TNF-α (P=0.000). Similarly, GG carriers of rs464218 with increased sortilin levels were found to be at increased risk for CHD (P=0.014). The levels of IL-1β (P=0.025) and IL-6 (P=0.015) were also increased in these patients. Conclusion: Our findings reveal that high sortilin levels may interact with inflammatory response to contribute to the occurrence of CHD. Considering that our clinical evidence suggests for the first time that sortilin involves in inflammatory response in CHD, the mechanistic role of sortilin in the progression of CHD deserves detailed investigation.

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Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Cited by 46 publications

References 36 publications

Dimerization of sortilin regulates its trafficking to extracellular vesicles

Dimerization of sortilin regulates its trafficking to extracellular vesicles

Transcriptional control of intestinal cholesterol absorption, adipose energy expenditure and lipid handling by Sortilin

<p>The Association Between Sortilin and Inflammation in Patients with Coronary Heart Disease</p>

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