Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Nozue, Tsuyoshi; Hashimoto, Hiroaki; Ogawa, Kazuyuki; Kujiraoka, Takeshi; Iwasaki, Takashi; Michishita, Ichiro

doi:10.5551/jat.33407

Cited by 34 publications

(27 citation statements)

References 40 publications

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“…A recent report showed that statin therapy in 90 statin-naive patients with CAD reduced sortilin serum levels by 12%. 19 In our study, treatment with statins or fibrates did not alter the association between serum sortilin and AAC, suggesting that the observed association of high serum sortilin with severe AAC might be independent of lipid abnormalities. This is in line with the cholesterol-independent role of sortilin in the development of experimental atherosclerosis 9 and vascular calcification, 11 and its genetic association with abdominal aortic aneurysm predisposition.…”

Section: Discussionsupporting

confidence: 38%

“…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: Discussionsupporting

confidence: 38%

Section: Introductionmentioning

confidence: 99%

Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Goettsch

Iwata

Hutcheson

et al. 2017

ATVB

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“…reported that 40 mg of rosuvastatin for 4 weeks increased PCSK9 levels by 37% in heterozygous FH 42 ) . Recently, we reported that 4 mg of pitavastatin and 20 mg of pravastatin significantly increased serum PCSK9 levels by 31% and 34%, respectively 43 ) . A recent metaanalysis demonstrated that a greater PCSK9 elevation was observed with lipophilic statins (atorvastatin, simvastatin, pitavastatin, and fluvastatin) compared with hydrophilic statins (rosuvastatin and pravastatin) 44 ) .…”

Section: Lipid-modifying Pharmacological Agents and Pcsk9 Concentratimentioning

confidence: 99%

Lipid Lowering Therapy and Circulating PCSK9 Concentration

Nozue

2017

J Atheroscler Thromb

Self Cite

102

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Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.

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“…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]. The increase in the plasma level of PCSK9 was correlated with the decrease of sSortilin/NTSR3 [62]. Since sSortilin/NTSR3 decreases the level of LDL through the internalization process [63], its decreased plasma level under statin treatment may counteract the increase of PCSK9 that is deleterious for the LDL level.…”

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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Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Cited by 34 publications

References 40 publications

Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Serum Sortilin Associates With Aortic Calcification and Cardiovascular Risk in Men

Lipid Lowering Therapy and Circulating PCSK9 Concentration

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

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