Prognostic value of soluble ST2 and soluble LR11 on mortality and cardiovascular events in peritoneal dialysis patients.

BACKGROUND: Although the soluble form of suppression of tumorigenicity 2 (sST2) and soluble low-density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11) have emerged as novel cardiovascular biomarkers in patients with cardiovascular disease, their prognostic value has not been fully investigated in peritoneal dialysis (PD) patients. METHODS: We included 74 prevalent PD patients from a prospective cohort and measured serum sST2 and sLR11 concentrations by an enzyme-linked immunosorbent assay. The association of these biomarkers and all-cause mortality and major adverse cardiac and cerebrovascular events (MACCEs) was evaluated. RESULTS: During a follow-up of 38.5 months, all-cause deaths and MACCEs were observed in 13 (17.6%) patients and 23 (31.3%) patients. Multivariable Cox analyses demonstrated that greater sST2 was independently associated with higher risk of all-cause mortality (≥75.8 ng/mL; hazard ratio [HR] = 5.551; 95% confidence interval [CI] = 1.360-22.660) and MACCEs (≥72.5 ng/mL; HR = 4.609; 95% CI = 1.608-13.208). Furthermore, sST2 showed additive predictive value for mortality to the base model including traditional risk factors (net reclassification index = 0.598, P = 0.04). sLR11 was not significantly associated with all-cause mortality or MACCE. CONCLUSIONS: sST2, but not sLR11, indicated a significant prognostic value for all-cause mortality and cardiovascular events in PD patients. Further research is needed to validate emerging biomarkers in these populations.

Impact of LR11 as Residual Risk on Long-Term Clinical Outcomes in Patients with Coronary Artery Disease Treated with Statins after First Percutaneous Coronary Intervention.

Cardiovascular events still occur despite statin-based lipid-lowering therapy in patients with coronary artery disease (CAD). LR11, a member of the low-density lipoprotein receptor family, is a novel marker for the proliferation of intimal smooth muscle cells, which are critical to atherosclerotic plaque formation. We evaluated the impact of LR11 on long-term clinical outcomes in CAD patients treated with statins after percutaneous coronary intervention (PCI).This study included 223 consecutive CAD patients (age, 64.5 ± 9.6 years; male, 81.2%) treated with statin after first PCI between March 2003 and December 2004 at our institution. Patients were stratified to two groups according to LR11 levels (median). Composite cardiovascular disease (CVD) endpoints that included cardiovascular death, non-fatal acute coronary syndrome and non-fatal stroke were compared between groups.The rate of CVD endpoints was significantly higher in the high LR11 group (log-rank, P = 0.0029) during the median follow-up period of 2844 days. Multivariate Cox regression analysis showed that a higher LR11 level was significantly associated with adverse clinical outcomes (adjusted hazard ratio for composite CVD endpoints, 2.47; 95% confidence interval, 1.29-4.92; P = 0.006).Elevated levels of LR11 were significantly associated with long-term clinical outcomes among CAD patients treated with statins after first PCI.

Relationship between normal weight obesity and mild cognitive impairment is reflected in cognitive-related genes in human peripheral blood mononuclear cells.

AIM: Obesity contributes to the development of mild cognitive impairment, but the potential role of normal weight obesity in this disease has not been explored in humans. The aim of the study was to reveal the relationship between normal weight obesity and mild cognitive impairment in elderly individuals. METHODS: This study consisted of 360 patients with amnestic mild cognitive impairment and 360 cognitively normal controls. Normal weight obesity was defined as having metabolic syndrome but a normal weight. Metabolic health meant having no metabolic syndrome. Reverse transcription quantitative real-time polymerase chain reaction was adopted to measure the messenger RNA expression of four cognitive-related genes (amyloid precursor protein, cyclic adenosine monophosphate-responsive element-binding protein 1, sortilin-related receptor 1, and synapsin I) in peripheral blood mononuclear cells. RESULTS: Normal weight obesity was related to a higher risk of amnestic mild cognitive impairment (odds ratio = 3.14, 95% confidence interval: 2.13-4.60). In the patients, the expression of each gene in the peripheral blood mononuclear cells was linearly related to Mini-Mental State Examination and Montreal Cognitive Assessment scores (P < 0.05). The expression of these genes in the patients with metabolic health deviated from the normal levels found in the controls (P < 0.05), and the deviations were more significant in the patients with normal weight obesity (P < 0.05). CONCLUSION: Normal weight obesity may be a potential risk factor for amnestic mild cognitive impairment in elderly. This relationship was reflected in the abnormal expression of several cognitive-related genes in peripheral blood mononuclear cells.

Association of Serum SorLA with Intimal Hyperplasia after Carotid Endarterectomy Operation: A Retrospective Analysis.

BACKGROUND: To study the relevance between serum sorting protein-related receptor containing the low-density lipoprotein receptor class A (SorLA) and intimal hyperplasia (IH) after carotid endarterectomy (CEA) operation. METHODS: Seventy-nine carotid artery stenosis patients receiving CEA operation from September 2013 to March 2015 were included. Serum SorLA level was detected by enzyme linked immunosorbent assay method preoperatively. All the 79 patients received regular follow-up to diagnose the IH of target lesions, postoperatively. Based on the follow-up data, the patients were divided into IH group (n = 10) and non-IH group (n = 69). Serum SorLA levels were analyzed using t-test. Receiver-operating characteristic curve was applied to determine the value of serum SorLA to predict the occurrence of IH after CEA operation. RESULTS: Patients in severe IH group had a higher level of serum SorLA than patients in non-IH group (1.648 ± 0.246 ng/mL vs. 1.278 ± 0.281 ng/mL, P < 0.001). When 1.44 ng/mL was designated as the cutoff value of serum SorLA, the predicting value had a sensitivity of 90% and a specificity of 73.5%. CONCLUSIONS: High serum SorLA level is related to IH after CEA operation. A serum SorLA level of 1.44 ng/mL can be used as a predicting index of postoperative IH.

G-CSF induces the release of the soluble form of LR11, a regulator of myeloid cell mobilization in bone marrow.

Granulocyte colony-stimulating factor (G-CSF) induces the mobilization of leukocytes from the bone marrow (BM) to the circulation by a yet incompletely understood mechanism. Here, we describe that the membrane-bound receptor LR11 is highly expressed in human myeloid cells and that the shed soluble form of LR11 (sLR11) is a modifier of myeloid cell migration. In the process of leukocyte mobilization by G-CSF treatment, circulating sLR11 levels are transiently elevated in humans and mice. Moreover, following G-CSF treatment, the sLR11 levels in patients show significant positive correlation with the numbers of mobilized leukocytes. The changes of LR11 levels in BM cells and of sLR11 released into the BM fluid of mice correlate tightly with the changes in circulating sLR11 levels. G-CSF dose-dependently enhanced sLR11 release from HL-60 cells, which in turn accelerated cell migration. Finally, cooperatively with tumor necrosis factor-α (TNF-α) and G-CSF, sLR11 increased the attachment of floating cells (HL-60 and U937) to endothelial cells. We propose that sLR11 is a novel candidate modifier of G-CSF-mediated mobilization of hematologic cells. Identification of sLR11 as a regulatory component of G-CSF-mediated hematologic cell mobilization may facilitate further improvement of hematologic stem cell collection for clinical applications.

[Novel biomarker for pathological immature cells--soluble form of LR11].

LR11 (also called SorLA or SORL1), a member of the LDL receptor family, was originally discovered in 1996 from genes specifically expressed in the intimal smooth muscle cells of atherosclerotic plaques. The soluble form of LR11 (sLR11) as well as the membrane-bound form plays a key role in the phenotype conversion of medial smooth muscle cells into intimal smooth muscle cells through the activation of urokinase receptor/integrin-mediated intracellular pathways. The levels of sLR11 in serum or CSF are increased in patients with atherosclerotic diseases, Alzheimer's disease or malignant diseases including acute leukemias. The recently developed ELISA system using two specific antibodies against LR11 made it possible to measure sLR11 quantitatively and stably for many samples. Thus, a novel clinical examination is expected to detect the pathological immature cells important for the pathophysiology of the above diseases. The soluble receptor-based clinical approach, together with basic studies about the structure-function relationship, may shed light on the development of novel target therapy against pathological immature cells in the science fields of so far independently categorized diseases.

A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene and bone mineral density in Japanese male workers.

OBJECTIVES: Both genetic and lifestyle factors have been shown to influence bone mineral density (BMD). We investigated the correlations between BMD and low-density lipoprotein receptor-related protein 5 (LRP5) A1330V (rs3736228) polymorphism, exercise, smoking, and alcohol intake in Japanese male workers. METHODS: The subjects were 829 male employees (aged 20-59 years) of a large-scale integrated manufacturing facility in Japan. BMD was measured at the nondominant radius by dual-energy X-ray absorptiometry. Lifestyle information was obtained by a questionnaire at the same time, and genomic DNA was isolated from peripheral leukocytes. RESULTS: Mean ± standard deviation (SD) BMD was 0.557 ± 0.059 g/cm(2). The genotype frequencies of LRP5 gene polymorphism were 51, 42, and 7% for AA, AV, and VV, respectively. Analysis of variance and post hoc Tukey test indicated that mean BMD was significantly lower in subjects with VV genotype than in those with AA genotype (0.540 ± 0.048 versus 0.562 ± 0.062 g/cm(2)). According to multiple linear regression analysis, LRP5 A1330V polymorphism was an independent determinant of BMD, after adjusting for age, body mass index (BMI), and lifestyle variables. Exercise (past or current) also influenced BMD. CONCLUSIONS: These findings suggest that LRP5 A1330V polymorphism and exercise may influence BMD in Japanese male workers.

A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol.

OBJECTIVE: A rare mutation in low-density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesized that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C). METHODS AND RESULTS: Twelve common (minor allele frequency > or =0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (P=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex-, and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations - 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (P=0.0268, P=0.0476, and P=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex-, and BMI-adjusted LDL-C (SE=0.05, P=0.0038). CONCLUSIONS: Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation.

Development of an immunoassay for the quantification of soluble LR11, a circulating marker of atherosclerosis.

BACKGROUND: Vascular smooth muscle cells (SMCs) migrate from the arterial media to the intima in the progression of atherosclerosis, and dysfunction of SMCs leads to enhanced atherogenesis. A soluble form of the LDL receptor relative with 11 ligand-binding repeats (sLR11) is produced by the intimal SMCs, and the circulating concentrations of sLR11 likely reflect the pathophysiological condition of intimal SMCs. Furthermore, polymorphism of the LR11 gene has been found to be related to the onset of Alzheimer disease. This study describes the development of a sandwich immunoassay for quantifying sLR11 in human serum and cerebrospinal fluid. METHODS: We used synthetic peptides or DNA immunization to produce monoclonal antibodies (MAbs) A2-2-3, M3, and R14 against different epitopes of LR11. RESULTS: sLR11 was immunologically identified as a 250-kDa protein in human serum and cerebrospinal fluid by SDS-PAGE separation, and was purified from serum by use of a receptor-associated protein and MAb M3. An immunoassay for quantification of sLR11 with a working range of 0.25-4.0 microg/L was developed using the combination of MAbs M3 and R14. Treatment of serum with 5.25% n-nonanoyl-N-methyl-d-glucamine reduced the matrix effects of serum on the absorbance detection in the ELISA system. The linear dynamic range of the ELISA spanned the variation of circulating sLR11 concentrations in individuals with atherosclerosis. CONCLUSIONS: A sandwich ELISA was established for quantifying sLR11 in serum and cerebrospinal fluid. This technique provides a novel means for assessing the pathophysiology of atherosclerosis, and possibly neurodegenerative diseases.

Circulating soluble LR11, a differentiation regulator for vascular cells, is increased during pregnancy and exaggerated in patients with pre-eclampsia.

BACKGROUND: Pre-eclampsia is a pregnancy-specific disease characterized by onset of hypertension and proteinuria, sometimes progressing into damaging other organs. Here, we investigated the pathological significance of the soluble fragment of LR11 (sLR11), a cell differentiation regulator, in comparison to circulating IL-6 and TNF-α, in pre-eclampsia. METHODS: The study was conducted in a cross-sectional research design with fourteen pre-eclampsia patients and fifty healthy pregnant subjects. Pre-eclampsia was defined as hypertensive disorders in pregnancy at over 20 weeks of gestation with proteinuria. RESULTS: Plasma levels of sLR11 as well as IL-6 in pre-eclampsia were increased compared with those in the healthy pregnant subjects at the first, the second, and the third trimester. Receiver operating characteristic analysis for the detection of pre-eclampsia among third-trimester subjects showed that the areas under the curves of sLR11 and IL-6 were equivalent. sLR11 and IL-6 correlated positively with TNF-α in healthy pregnant subjects. In the pre-eclampsia patients, there was neither a correlation between sLR11 and IL-6 nor between sLR11 and TNF-α. CONCLUSIONS: sLR11 increases during pregnancy, with levels further exaggerated in pre-eclampsia, and may be related to the pathology of pre-eclampsia.

Levels of circulating soluble LR11, a regulator of smooth muscle cell migration, are highly associated with atherosclerotic plaques in patients with carotid artery stenosis.

BACKGROUND: The levels of plasma sLR11, released from intimal SMCs, are positively associated with intima-media thickness (IMT) in asymptomatic subjects. We have evaluated the yet unknown pathological significance of sLR11 for plaque conditions in patients with carotid artery stenosis. METHODS: The presence of LR11 in carotid plaques was investigated using autopsy specimens. A clinical ultrasonography study for elucidating relationships between sLR11 and plaque condition was performed in 46 patients. RESULTS: Immunohistochemistry showed high levels of LR11 in SMCs within thickened intima and at the media-intima border of atherosclerotic carotid plaques. The levels of sLR11 in patients were clearly elevated compared to healthy controls. Univariate analysis of sLR11 revealed significant positive correlation with plaque score and a tendency to correlate with the stenotic fraction. Univariate and multiple regression analyses of plaque scores showed that sLR11, maximum IMT, and HDL-cholesterol independently determined plaque score. Finally, univariate analysis of initial sLR11 levels for changes in imaging markers after one-year follow-up showed that initial sLR11 levels significantly correlated with stenotic fraction progression. CONCLUSIONS: The levels of sLR11, abundantly expressed in carotid atherosclerotic plaques, are highly associated with increased plaque score. sLR11 levels may be predictive of plaque conditions in patients with advanced carotid atherosclerosis.

Anti-AChR, MuSK, and LRP4 antibodies coexistence: A rare and distinct subtype of myasthenia gravis from Indian subcontinent.

BACKGROUND: Myasthenia gravis is B-cell mediated autoimmune disease and is associated with antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) in the postsynaptic membrane at the neuromuscular junction. There are few studies on the concurrent presence of two positive antibodies in the sera of patients with myasthenia gravis. CASE DESCRIPTION: A 32-year male admitted to the hospital with progressive neuromuscular weakness. He was diagnosed with Myasthenia gravis disorder mimicking Amyotrophic Lateral Sclerosis. We herein report a rare co-existence of three antibodies (anti-AChR, MuSK, and LRP4 antibodies) in the patient's serum. CONCLUSION: We present a detailed clinical and laboratory analysis of the patient. This case report will emphasize the importance of evaluating anti-MuSK and anti-LRP4 antibodies even in patients with anti-AChR antibodies.

Exploring the sortilin related receptor, SorLA, in depression.

BACKGROUND: Studies of individual biomarkers for depression have shown insufficient sensitivity and specificity for clinical use, and most likely combinations of biomarkers may provide a better signature. The sorting-related receptor with A-type repeats (SorLA) is a well-studied pathogenic factor for Alzheimer's. SorLA belongs to the Vps10p domain receptor family, which also encompasses sortilin and SorCS1-3. All family members have been implicated in neurological and mental disorders. Notably, the SORCS3 gene is genome-wide significantly associated with depression and serum protein levels of sortilin are reduced in depressed individuals. SorLA regulates the activity of neurotrophic factors and cytokines and we hence speculated that SorLA might be implicated in depression. METHODS: Serum SorLA levels were measured in two well-defined clinical samples using ELISA. Generalized linear models were used in the statistical analyses. RESULTS: We identified a multivariate model to discriminate depressed individuals from healthy controls. Interestingly, the model consisted of serum SorLA levels and additional four predictors: previous depressive episode, stressful life events, serum levels of sortilin and VEGF. However, as an isolated factor, we observed no significant difference in SorLA levels between 140 depressed individuals and 140 healthy controls. Nevertheless, we observed a significant increase in SorLA levels following 12 weeks of treatment with nortriptyline, but not escitalopram. LIMITATIONS: The number of biomarkers included in the multivariate model for depression and lack of replication limit our study. CONCLUSIONS: Our results suggest SorLA as one of five factors that in combination may support the depression diagnosis, but not as an individual biomarker for depression or treatment response.

Soluble LR11 associates with aortic root calcification in asymptomatic treated male patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Despite statin treatment, a high prevalence of severe vascular calcification is found in patients with familial hypercholesterolemia (FH). We assessed the relation between the circulating soluble form of low-density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11), a risk factor for cardiovascular disease, and vascular calcification in asymptomatic statin-treated heterozygous FH patients. METHODS: In 123 asymptomatic heterozygous FH patients (age 40-69 years), aortic root (ARC), aortic valve (AVC) and coronary artery calcification (CAC) were determined with CT-based calcium scoring expressed in Agatston units. Plasma sLR11 levels were measured by sandwich ELISA. RESULTS: Seventy-three patients displayed ARC, 48 had AVC and 96 CAC. Plasma sLR11 levels were positively correlated with the presence of ARC (r = 0.2, p = 0.03), but not with AVC or CAC. The correlation between sLR11 levels and ARC was restricted to male FH patients (r = 0.31, p = 0.006). Multivariate logistic analyses showed that the association of plasma sLR11 with the presence of ARC was independent of other determinants (Adjusted Odds Ratio, 2.01 (95% CI = 1.28-3.16) p = 0.002). CONCLUSIONS: Plasma sLR11 is associated with ARC in male FH patients and may be mechanistically involved in the differential distribution of atherosclerotic lesions in the vasculature.

Circulating soluble form of LR11, a regulator of smooth muscle cell migration, is a novel marker for intima-media thickness of carotid arteries in type 2 diabetes.

BACKGROUND: Smooth muscle cell (SMC) migration from the media to the intima, a process affecting plaque stability in advanced-stage atherosclerosis, is under the control of LR11. To delineate the clinical significance of the circulating soluble form of LR11 (sLR11) in patients with type 2 diabetes (T2D), we analyzed the correlation of sLR11 levels with intima-media thickness (IMT) of carotid arteries. METHODS: Plasma sLR11 levels were measured in 165 patients with T2D (mean age 56.2±10.4 y, 58.2% males, and BMI 24.6±3.6) by ELISA. Averaged IMT levels of common carotid arteries were determined by ultrasonography. RESULTS: Circulating sLR11 levels were 9.8±3.5ng/ml, and correlated positively with the classical atherosclerosis risk factors age, sex, systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C), fasting plasma-glucose (FPG), and glycosylated hemoglobin. Multivariate linear regression analysis indicated that only FPG was associated with sLR11; sLR11 correlated positively with IMT, together with age and FPG, but less with LDL-C. Among the serum risk factors for IMT, multivariate linear regression analysis uncovered that sLR11 was independently associated with IMT. Subsequent logistic analysis revealed that FPG correlated best with IMT values at a cut-off of 0.80mm and sLR11 at a cut-off of 0.90mm, respectively, while LDL-C showed lower discriminatory power at any IMT cut-off values. CONCLUSION: Increased sLR11 concentrations are highly associated with increased IMT as well as with FPG in middle-aged, non-obese patients with T2D. Circulating sLR11 may be a novel marker representing the pathophysiology of intimal SMCs in patients with T2D.

Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome.

UNLABELLED: Essentials (NZWxBXSB)F1 male mice develop antibodies beta2-glycoprotein I (ß2GPI) and hypertension. A1-A1 is a soluble analogue of ApoE receptor 2 with a high affinity for ß2GPI/antibody complexes. A1-A1 improved blood pressure and arterial elastance in (NZWxBXSB)F1 male mice. A1-A1 had no adverse effects on the hemodynamics of healthy mice. SUMMARY: Background Antiphospholipid syndrome (APS) is diagnosed based on the presence of antiphospholipid antibodies and clinical thrombosis or fetal loss during pregnancy. Lupus-prone (NZWxBXSB)F1 male mice are the mouse model of spontaneous APS. They develop anti-ß2GPI antibodies, microinfarcts and hypertension. ApoER2 is a receptor that contributes to anti-ß2GPI-dependent thrombosis in APS by down-regulating endothelial nitric oxide synthase activation. Objectives A1-A1 is a small protein constructed from two identical ligand-binding modules from ApoER2, containing the binding site for ß2GPI. We studied how treatment with A1-A1 affects the development of hypertension in (NZWxBXSB)F1 male mice. Methods We treated (NZWxBXSB)F1 male mice with A1-A1 for up to 4 weeks and examined changes in hemodynamics by left ventricular pressure-volume loop measurements. Results We observed improvements in blood pressure in the A1-A1 treated mice. A1-A1 prevented the deterioration of arterial elastance by decreasing systemic resistance and improving vessel compliance. We did not detect any adverse effects of the treatment in either male mice or in apparently healthy female (NZWxBXSB)F1 mice. Conclusions We demonstrated that A1-A1, which is a soluble analog of ApoER2 that binds pathological ß2GPI/anti-ß2GPI complexes, has a positive impact on hemodynamics in lupus-prone mice with spontaneous anti-ß2GPI antibodies and hypertension.

Prognostic impact of circulating soluble LR11 on long-term clinical outcomes in patients with coronary artery disease.

BACKGROUND: LR11, a member of LDL receptor family, is a novel marker of the proliferation of intimal smooth muscle cells (SMCs). LR11 is released in soluble form (sLR11) by proteolytic shedding and has biological activity toward SMC migration. We previously showed that circulating sLR11 positively correlates with carotid intima-medial thickness (IMT) independently of classical atherosclerotic risk factors and that it significantly associates with the severity of CAD. However, the association between sLR11 and long-term clinical outcomes remain uncertain. METHODS AND RESULTS: This study included 438 consecutive patients (mean age, 65.8 ± 9.6 y; male, 82.4%) who underwent coronary intervention between March 2003 and December 2004 at our institution. The patients were assigned to quartiles according to pre-procedural sLR11 values. The primary endpoints were composite cardiovascular disease (CVD) endpoints including cardiovascular death, non-fatal acute coronary syndrome and non-fatal stroke. During median follow-up of 2876 days, composite CVD endpoints occurred 97 (22.1%) patients including 41 (9.4%) with cardiovascular disease (CVD)-related death, 36 (8.2%) non-fatal ACS and 20 (4.6%) non-fatal strokes. The hazard ratio (HR) for composite CVD endpoints significantly and dose-dependently increased with sLR11 levels (p for trend = 0.0077). A higher logarithm-transformed sLR11 value was associated with a greater risk of composite CVD endpoints, and the increased number of adverse long-term clinical outcomes persisted even after adjustment for other independent variables (HR 1.87 95%CI 1.02-3.31, p = 0.0435). CONCLUSIONS: Elevated sLR11 levels were significantly associated with higher long-term adverse cardiac events in patients with CAD. Further extensive studies are expected to elucidate the mechanistic role of sLR11 and its clinical value as a prognostic marker in the development of atherosclerosis.

Soluble LR11 is a novel biomarker for vascular lesions late after Kawasaki disease.

OBJECTIVE: Coronary artery lesions (CALs) and a risk for early onset of atherosclerosis are major concerns following Kawasaki disease (KD). Intimal smooth muscle cells (SMCs) have an important role in vascular lesions in KD. It is known that soluble LR11 (sLR11) is a novel biomarker for vascular lesions and LR11 is markedly expressed in intimal SMCs in atherosclerotic lesions. In this study, we hypothesized that sLR11 reflects the presence of vascular lesions late after KD. METHODS: Twenty-three age-matched controls (group 1) and 59 patients with a history of KD were enrolled; 36 with KD had normal coronary arteries or regressed aneurysms (group 2), and 23 had CALs (group 3). RESULTS: Serum sLR11 levels in group 3 (median, interquartile range (IQR): 11.1 ng/mL, 9.3-13.9 ng/mL) were significantly higher than those in groups 1 (8.4 ng/mL, 7.1-10.2 ng/mL, p < 0.001) and 2 (9.0 ng/mL, 7.7-10.1 ng/mL, p < 0.01). Levels of sLR11 were positively correlated with levels of high-sensitivity C-reactive protein (r = 0.480, p < 0.01) and lipoprotein (a) (r = 0.486, p < 0.01). CONCLUSION: These findings suggest that sLR11 reflects the development of vascular lesions in patients with serious CALs.

Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is a major complication in patients with type 2 diabetes (T2D), especially in those with obesity. Plasma soluble low density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of atherosclerosis and has been linked to the metabolism of triglyceride-rich lipoproteins, adiposity, and vascular complications in T2D. We aimed to determine the effect of diet-induced weight loss on plasma sLR11 levels in overweight and obese individuals with T2D. METHODS: Plasma sLR11 levels were determined in 64 individuals with T2D and BMI >27 kg/m2 before and after a 20-week weight loss diet. As a reference, sLR11 levels were also determined in 64 healthy, non-obese controls, matched as a group for age and sex. RESULTS: Median plasma sLR11 levels of the T2D study-group at baseline (15.4 ng/mL (IQR 12.9-19.5)) were higher than in controls (10.2 (IQR: 8.7-12.2) ng/mL; p = 0.001). The diet resulted in a weight loss of 9.7 ± 5.2% (p = 0.001) and improved CVD risk factors. sLR11 levels were reduced to 13.3 ng/mL (IQR 11.0-17.1; p = 0.001). Changes in sLR11 levels positively associated with changes in non-HDL cholesterol (B = 1.54, R2 = 0.17, p = 0.001) and HbA1c (B = 0.07, R2 = 0.11, p = 0.007), but not with weight loss (B = 0.04, R2 = 0.05, p = 0.076). The changes in non-HDL cholesterol and HbA1c together explained 24% of the variance of sLR11 reduction (p = 0.001). CONCLUSIONS: Weight loss dieting in overweight and obese individuals with T2D resulted in a reduction in plasma sLR11 levels that was associated with improvements in lipid-profile and glycemic state.

Prognostic impact of serum soluble LR11 in newly diagnosed diffuse large B-cell lymphoma: A multicenter prospective analysis.

BACKGROUND: LR11 (also called SorLA or SORL1) is a type I membrane protein, originally identified as a biomarker for atherosclerosis and Alzheimer's disease. We recently found that LR11 was specifically expressed in Diffuse Large B-cell lymphoma (DLBCL) cells, and high serum sLR11 concentrations in retrospective cohort indicated inferior survival. In this study, we prospectively validated the clinical impact of serum sLR11 in 97 patients with newly-diagnosed, untreated DLBCL. RESULTS: Serum sLR11 concentrations were increased in DLBCL patients compared to normal controls (mean±SD: 21.2±27.6 vs. 8.8±1.8ng/ml, P<0.0001), and significantly reduced at remission (mean±SD: 17.4±16.4 vs. 10.9±4.5ng/ml, P=0.02). Increased serum sLR11 concentrations were affected by tumor burden and bone marrow invasion. The 2-y OS and PFS were significantly lower in patients with high sLR11 concentrations (≤18.1ng/ml vs. >18.1ng/ml; 2-y OS: 89.0% vs. 56.4%, P<0.0001; 2-y PFS: 85.8% vs. 56.9%, P<0.0001). CONCLUSIONS: Serum sLR11 is a tumor-derived biomarker for predicting the survival of newly diagnosed patients with DLBCL.