Soluble sortilin is released by activated platelets and its circulating levels are associated with cardiovascular risk factors

Ogawa, Kazuyuki; Ueno, Takayoshi; Iwasaki, Takashi; Kujiraoka, Takeshi; Ishihara, Misa; Kunimoto, Satoshi; Takayama, Tadateru; Kanai, Takashi; Hirayama, Atsushi; Hashimoto, Hiroaki

doi:10.1016/j.atherosclerosis.2016.03.041

Cited by 40 publications

(51 citation statements)

References 42 publications

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“…In our cohort, sortilin serum levels were positively correlated with CRP, TC and LDL-C levels, the data consistent with observations in a previously published study. 12 Nevertheless, when CRP, TC or LDL-C levels were added to the multivariate model, along with other known AAC risk factors, the sortilin-AAC association remained significant. A recent report showed that statin therapy in 90 statin-naive patients with CAD reduced sortilin serum levels by 12%.…”

Section: Discussionmentioning

confidence: 97%

“…Importantly, experimental data reveals a role for sortilin in type 2 diabetes by regulating insulin resistance 8 as well as in the development of atherosclerotic lesions by controling the interleukin-6 release from inflammartory cells 9 , LDL-uptake into macrophages, 10 or involvement in platelet activation 12 - the risk factors for cardiovascular events that may contribute to the sortilin association with MACCE risk. In our cohort, high serum sortilin was associated with MACCE independently of hypertension, diabetes mellitus, or decreased testosterone levels - all cardiovascular risk factors.…”

Section: Discussionmentioning

confidence: 99%

“…11 A recent study also reported a correlation of plasma sortilin with C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C) – both cardiovascular risk factors. 12 …”

Section: Introductionmentioning

confidence: 99%

“…However, direct clinical evidence of serum sortilin as a marker for cardiovascular risk as well as of the role of LDL cholesterol and vascular calcification as potential confounders of such an association is lacking. 12, 19 Therefore, the primary object of the current study was to evaluate the association of serum sortilin levels with the prospectively assessed risk of major adverse cerebro-cardiovascular events (MACCE) and with severe AAC in a community-dwelling cohort of men aged ≥50.…”

Section: Introductionmentioning

confidence: 99%

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Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Goettsch

Iwata

Hutcheson

et al. 2017

ATVB

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Objective GWAS and preclinical studies demonstrated a role of sortilin in lipid metabolism, inflammation, and vascular calcification – all cardiovascular risk factors. We evaluated the association of serum sortilin levels with the risk of major adverse cerebrovascular and cardiovascular events (MACCE) and the severity of abdominal aortic calcification (AAC). Approach and Results A cohort of community-dwelling men aged ≥50 (n=830) was assessed. At baseline, sortilin levels were measured by ELISA, and AAC was assessed on lateral spine scans obtained by dual-energy X-ray absorptiometry. Men aged ≥60 (n=745) were followed up prospectively for the incidence of MACCE. During the median follow-up of 7.9 years, 76 MACCE occurred. The unadjusted incidence of MACCE across increasing sortilin quartiles was: 8.0; 7.4; 19.8, and 20.3 per 1000 person-years. In multivariate-adjusted analysis, sortilin associated with increased risk of MACCE (HR=1.70 per SD; 95%CI: 1.30–2.20, p<0.001). The third and fourth quartiles associated with 3.42-fold (95%CI: 1.61–7.25, p<0.005) and 3.82-fold (95%CI: 1.77–8.26, p<0.001) higher risk of MACCE compared to the first quartile. High sortilin also predicted MACCE independent of traditional Framingham risk factors. Higher sortilin associated with higher odds of severe AAC (score>5) after adjustment for confounders (OR=1.43 per SD, 95%CI: 1.10–1.85, p<0.01). The highest sortilin quartile associated with two-fold higher odds of severe AAC (vs. three lower quartiles combined). After adjustment for LDL-cholesterol the odds of severe AAC remained significant. Conclusions In older men, higher serum sortilin levels associated with higher MACCE risk and severe AAC independently of relevant confounders, including C-reactive protein and LDL-cholesterol. This finding however, needs to be validated in other cohorts.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

“…11 A recent study also reported a correlation of plasma sortilin with C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C) – both cardiovascular risk factors. 12 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Goettsch

Iwata

Hutcheson

et al. 2017

ATVB

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“…Indeed, a very recent work reported that the plasma level of sSortilin/NTSR3 was increased by activated platelets in association with cardiovascular risk from patients with hypertension and dyslipidemia [60]. Interestingly, statin treatment of patients with cardiovascular risks enhanced the amount of plasma Proprotein Convertase Subtilisin/kexin type 9 (PCSK9), a convertase responsible for the degradation of low-density lipoprotein (LDL) receptors [61].…”

Section: Other Functions Of Ssortilin/ntsr3mentioning

confidence: 99%

Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation

Béraud-Dufour

Devader

Massa

et al. 2016

IJMS

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The aim of the present review is to unravel the mechanisms of action of the soluble form of the neurotensin (NT) receptor-3 (NTSR3), also called Sortilin, in numerous physiopathological processes including cancer development, cardiovascular diseases and depression. Sortilin/NTSR3 is a transmembrane protein thought to exert multiple functions both intracellularly and at the level of the plasma membrane. The Sortilin/NTSR3 extracellular domain is released by shedding from all the cells expressing the protein. Although the existence of the soluble form of Sortilin/NTSR3 (sSortilin/NTSR3) has been evidenced for more than 10 years, the studies focusing on the role of this soluble protein at the mechanistic level remain rare. Numerous cancer cells, including colonic cancer cells, express the receptor family of neurotensin (NT), and particularly Sortilin/NTSR3. This review aims to summarize the functional role of sSortilin/NTSR3 characterized in the colonic cancer cell line HT29. This includes mechanisms involving signaling cascades through focal adhesion kinase (FAK), a key pathway leading to the weakening of cell–cell and cell–extracellular matrix adhesions, a series of events which could be responsible for cancer metastasis. Finally, some future approaches targeting the release of sNTSR3 through the inhibition of matrix metalloproteases (MMPs) are suggested.

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Complicated trafficking behaviors involved in paradoxical regulation of sortilin in lipid metabolism

Sun

Yang

Xie

et al. 2019

Journal Cellular Physiology

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This review aims to summarize and discuss the most recent advances in our understanding of the underlying mechanisms of the paradoxical effects of sortilin on lipid metabolism. The vacuolar protein sorting 10 protein (Vps10p) domain in the sortilin protein is responsible for substrate binding. Its cytoplasmic tail interacts with adaptor molecules, and modifications can determine whether sortilin trafficking occurs via the anterograde or retrograde pathway. The complicated trafficking behaviors likely contribute to the paradoxical roles of sortilin in lipid metabolism. The anterograde pathway of sortilin trafficking in hepatocytes, enterocytes, and peripheral cells likely causes an increase in plasma lipid levels, while the retrograde pathway leads to the opposite effect. Hepatocyte sortilin functions via the anterograde or retrograde pathway in a complicated and paradoxical manner to regulate apoB‐containing lipoprotein metabolism. Clarifying the regulatory mechanisms underlying the trafficking behaviors of sortilin is necessary and may lead to artificial sortilin intervention as a potential therapeutic strategy for lipid disorder diseases. Conclusively, the paradoxical regulation of sortilin in lipid metabolism is likely due to its complicated trafficking behaviors.

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Soluble sortilin is released by activated platelets and its circulating levels are associated with cardiovascular risk factors

Cited by 40 publications

References 42 publications

Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation

Complicated trafficking behaviors involved in paradoxical regulation of sortilin in lipid metabolism

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