Deficiency of Nardilysin in the Liver Reduces Serum Cholesterol Levels.

Nardilysin (NRDC) has been shown to be involved in post-translational histone modifications, in addition to enhancement in ectodomain shedding of membrane-anchored protein, which play significant roles in various pathophysiology, including glucose homeostasis, inflammatory diseases and cancer. The present study sought to determine roles of NRDC in the liver on lipid and lipoprotein metabolism. We established liver-specific NRDC deficient mice by use of NRD1 floxed mice and albumin promoter-Cre recombinase (Cre) transgenic mice, and found that their serum low-density lipoprotein (LDL) cholesterol levels were significantly lower than those in control littermate mice. In the liver, LDL receptor (LDLR) mRNA expression was significantly upregulated, while inducible degrader of LDLR (IDOL) and microsomal triglyceride transfer protein (MTP) mRNA expression was significantly downregulated, in liver-specific NRDC deficient mice. Hepatic cell-surface LDLR expression levels were significantly elevated and serum pro-protein convertase subtilisin-kexin type 9 (PCSK9) levels were significantly reduced in mice with hepatic NRDC deficiency. In cultured hepatocytes, NRDC deficiency significantly reduced secreted PCSK9 and increased cell-surface LDLR expression. On the other hand, NRDC overexpression in cultured hepatocytes significantly increased secreted PCSK9 and lowered cell-surface LDLR expression. Thus, NRDC in murine hepatocytes appears to play key roles in cholesterol homeostasis, although the precise molecular mechanisms remain to be determined.

Association of Hypnotic Drug Use with Fall Incidents in Hospitalized Elderly Patients: A Case-Crossover Study.

We investigated whether use of hypnotic drugs, including benzodiazepine receptor agonists, as well as ramelteon and suvorexant are associated with fall incidents in elderly inpatients aged no less than 75 years, who were hospitalized at an acute care general hospital in Japan, between November 1st, 2016 and October 31st, 2017. Multivariate analysis results were reported as odds ratio (OR) with 95% confidence interval (CI). Following to a case-crossover study protocol, the time windows of the case and the control days were assigned to the day or the days, which are one day or 2-8 d before the fall incidents, respectively. In the enrolled 111 patients, the accumulated total available numbers of the cases and the control days were 111 and 554 patient days, respectively. Hypnotic drug use was significantly associated with fall incidents (OR: 2.85, 95% CI: 1.03-7.90, p = 0.04). Especially benzodiazepine receptor agonists (OR: 5.79, 95% CI: 1.52-22.1, p = 0.01) showed statistically significant association with fall incidents. In contrast, neither ramelteon (OR: 7.95, 95% CI: 0.72-87.9, p = 0.09) nor suvorexant (OR: 0.25, 95% CI: 0.06-1.06, p = 0.06) were significantly associated with fall incidents. Thus, benzodiazepine receptor agonists, but not ramelteon or suvorexant, showed significant association with fall incidents. Therefore, special care should be taken especially when benzodiazepine receptor agonists are administrated to elderly subjects. In contrast, fall risk may be much less in patients treated with ramelteon or suvorexant. These results could help us to conduct safer drug treatment for insomnia patients aged no less than 75 years.

Reduced Serum Cholesterol and Triglyceride Levels in a Choline-Deficient L-Amino Acid-Defined High-Fat Diet (CDAHFD)-Induced Mouse Model of Non-alcoholic Steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic seatohepatitis (NASH) is one of the major health problems world wide, because of increased abdominal obesity. To date, specific and effective medications to treat or prevent NAFLD/NASH have not been established. To identify appropriate molecular targets for that purpose, suitable animal models of NAFLD/NASH have been explored. A choline-deficient amino acid-defined high fat diet (CDAHFD)-induced mouse model of NASH has been developed. However, its relevance to human NASH, including serum lipid profiles, have not been clearly defined. In this study, we have revealed that mice fed CDAHFD showed significantly lowerd serum total cholesterol and triglyceride (TG) levels, in addition to reduced body weight (BW). Furthermore, hepatic microsomal triglyceride transfer protein (MTP) expression was significantly downregulated in CDAHFD-fed mice. Thus, the current CDAHFD-fed mouse model has points that are distinct from human NAFLD/NASH, in general, which is based upon abdominal obesity.

Effects of Ramelteon and Other Sleep-Promoting Drugs on Serum Low-Density Lipoprotein and Non-high-density Lipoprotein Cholesterol: A Retrospective Comparative Pilot Study.

Melatonin has been suggested to play important roles in lipid metabolism as well as circadian rhythm; however, very few studies explored the effects of ramelteon, a selective melatonin receptor agonist, on serum lipid profiles. In this study effects of ramelteon on serum lipid profiles were explored, comparing to those of other sleep-promoting drugs including benzodiazepines and non-benzodiazepines, in patients with insomnia. We retrospectively reviewed medical charts of outpatients who were treated with ramelteon (8 mg/d) or other sleep-promoting drugs for no less than 8 weeks during the period between October 1st, 2011 and September 30th, 2014, and compared the changes in serum lipid profiles between the two groups. Patients with regular dialysis or malignant diseases treated with cytotoxic anti-cancer drugs, or whose lipid-lowering drugs were altered during the study period, were excluded. Among 365 or 855 outpatients treated with ramelteon or other sleep-promoting drugs, 35 or 46 patients, respectively, had complete serum low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) data. Serum LDL-C was significantly reduced from 103.1±4.4 to 94.6±4.2 mg/dL (8.2% reduction, p<0.05, n=31) in the ramelteon group, and was not significantly changed (p=0.23, n=40) in the other sleep-promoting drug group. Non-HDL-C was significantly decreased from 138.8±6.0 to 130.6±4.9 mg/dL (5.9% reduction, p<0.05, n=32) in the ramelteon group, and was not significantly altered (p=0.29, n=42) in the other sleep-promoting drug group. Ramelteon, but not other sleep-promoting drugs, specifically lowers serum LDL-C and non-HDL-C levels.

Comparison of serum lipid management between elderly and non-elderly patients with and without coronary heart disease (CHD).

Serum lipid management in patients aged ≥ 75 has not been precisely explored. We, therefore, compared the serum lipid management between the two age groups with and without coronary heart disease (CHD). We, therefore, retrospectively reviewed medical charts of patients who were hospitalized in the departments of internal medicine during a period of 14 months. Serum lipid goal attainment was explored by applying the lipid goals for patients aged < 75 to those aged ≥ 75. In 1988 enrolled patients, 717 subjects (36.1%) were aged ≥ 75. Among them, 41.3% and 32.4% of the patients had CHD, 44.2% and 41.0% were primary prevention at high-risk, and 14.5% and 14.6% were primary prevention at moderate-risk in patients aged ≥ 75 and aged < 75, respectively. Serum LDL-C goal achievement rates in CHD were 66.9% and 65.0% in patients aged ≥ 75 and < 75, respectively (p = 0.334). In the primary prevention at high-risk, these rates were 73.5% and 63.3%, in patients aged ≥ 75 and < 75, respectively (p = 0.001). They were 77.9% and 58.1% in primary prevention at moderate-risk aged ≥ 75 and < 75, respectively (p < 0.001). In CHD, lipid-lowering medication subscription rates were significantly lower in patients aged ≥ 75 (60.1%) than those aged < 75 (73.8%, p < 0.001). In conclusion, in CHD, serum lipid goal attainment was comparable between the two age groups although the lipid-lowering drugs were less frequently prescribed in patients aged ≥ 75. Without CHD, it was significantly better in patients aged ≥ 75 than those aged < 75 although the lipid-lowering drug subscription rates were comparable between the two age groups.

Matrix Metalloproteinase-9 as a Marker for Plaque Rupture and a Predictor of Adverse Clinical Outcome in Patients with Acute Coronary Syndrome: An Optical Coherence Tomography Study.

OBJECTIVES: The present study sought to clarify the relationship between matrix metalloproteinase-9 (MMP-9) levels and plaque morphology demonstrated by optical coherence tomography (OCT), and to examine their prognostic impacts in patients with acute coronary syndrome (ACS). METHODS: MMP-9 levels were measured for patients with ACS (n = 249). Among 249 patients, 120 with evaluable OCT images were categorized into patients with ruptured plaques (n = 65) and those with nonruptured plaques (n = 55) on the basis of culprit lesion plaque morphology demonstrated by OCT. RESULTS: MMP-9 levels on admission were significantly higher in the rupture group than in the nonrupture group (p = 0.029). Although creatine kinase-MB (CK-MB) on admission was comparable between the groups, peak CK-MB was higher in the rupture group than in the nonrupture group (p < 0.001). By receiver operating characteristic curve analysis, the optimal cut-off value of MMP-9 to detect ruptured plaques was 65.5 ng/ml (p = 0.029). There was a nonstatistically significant trend toward increased cardiac death at 2 years (5.9 vs. 1.0%, p = 0.059) in patients with high MMP-9 (≥65.5 ng/ml) compared to those with low MMP-9 (<65.5 ng/ml). CONCLUSIONS: MMP-9 can differentiate ACS with ruptured plaques from nonruptured plaques, and MMP-9 may be a valuable predictor of long-term cardiac mortality in patients with ACS reflecting plaque rupture.

Serum Lipid Goal Attainment in Chronic Kidney Disease (CKD) Patients under the Japan Atherosclerosis Society (JAS) 2012 Guidelines.

AIM: According to the Japan Atherosclerosis Society 2012 guidelines (JAS2012-GL), chronic kidney disease (CKD) has newly been added to the high-risk group in terms of atherosclerotic cardiovascular diseases. We therefore explored the lipid target level achievement rates under the JAS2012-GL in real-world clinical practice. METHODS: We retrospectively reviewed the medical charts of patients who were hospitalized at the Nephrology Department at Kobe City Medical Center General Hospital in the period from April 1, 2012 to May 31, 2013 and explored the serum lipid target level achievement rates. Patients without lipid data or those undergoing regular dialysis because of chronic renal failure were excluded. In this study, the CKD group (CKD-G) did not include CKD patients under secondary prevention for coronary heart disease (CHD) or diabetes mellitus (DM). RESULTS: The CKD-G included 146 (81.1%) of the 180 enrolled patients. According to the JAS2012-GL, 100% of the CKD-G patients were categorized into the high-risk group, although only 12.1% of the CKD-G subjects were at high risk according to the JAS2007-GL. Under the JAS2012-GL, the LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) target level achievement rates for CKD-G were 71.4% and 68.1%, respectively. According to the JAS2007-GL, these rates were 81.3% and 79.1%, respectively, and, under both guidelines, these rates were 71.7% and 72.1% for primary prevention DM and 66.7% and 66.7% for CHD, respectively. CONCLUSIONS: After the revision of the JAS-GL in 2012, the LDL-C and non-HDL-C target level achievement rates for CKD-G were reduced by approximately 10%; however, they remained similar to those for DM and higher than those for CHD.

Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel prognostic biomarker in patients with ST-segment elevation acute myocardial infarction.

BACKGROUND: Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) level is a reliable prognostic biomarker in acute coronary syndrome. However, it is unclear whether its plasma level at acute phase is related to the long-term prognosis in patients with ST-segment elevation acute myocardial infarction (STEMI). METHODS AND RESULTS: We prospectively examined the relation between plasma sLOX-1 level on admission and prognosis in 153 consecutive STEMI patients admitted within 24 h of onset. Primary percutaneous coronary intervention was performed in 144 patients. The patients were divided into 2 groups by the median value (71 pg/ml) of plasma sLOX-1 level on admission [sLOX-1 level ≤71 pg/ml (n=77) and >71 pg/ml (n=76)], and were followed for median of 1,156 days. All-cause mortality and the combined endpoints of major adverse cardiovascular events (MACE) defined as cardiovascular mortality and recurrent MI were both significantly higher in patients with sLOX-1 values above median than in those below median (25.0% vs. 3.9%, P<0.001, and 19.4% vs. 6.5%, P=0.019 by log-rank test, respectively). Even after adjustment for confounders, a level of sLOX-1 above median was an independent predictor for all-cause mortality (hazard ratio (HR): 5.893; 95% confidence interval (CI): 1.665-20.854, P=0.006) and MACE (HR: 3.457; 95% CI: 1.164-10.270, P=0.030). CONCLUSIONS: Elevated plasma sLOX-1 level on admission independently predicts long-term all-cause mortality and MACE after STEMI.

MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo.

MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models.

MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice.

MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports have indicated that miR-33, which is located within the intron of sterol regulatory element-binding protein (SREBP) 2, controls cholesterol homoeostasis and may be a potential therapeutic target for the treatment of atherosclerosis. Here we show that deletion of miR-33 results in marked worsening of high-fat diet-induced obesity and liver steatosis. Using miR-33(-/-)Srebf1(+/-) mice, we demonstrate that SREBP-1 is a target of miR-33 and that the mechanisms leading to obesity and liver steatosis in miR-33(-/-) mice involve enhanced expression of SREBP-1. These results elucidate a novel interaction between SREBP-1 and SREBP-2 mediated by miR-33 in vivo.

Soluble lectin-like oxidized LDL receptor-1 (sLOX-1) as a valuable diagnostic marker for rupture of thin-cap fibroatheroma: verification by optical coherence tomography.

BACKGROUND: Relationships between plaque morphology on optical coherence tomography (OCT) and biomarker levels in the patients with acute coronary syndrome (ACS) have not been fully investigated. METHODS: ACS patients (n=128) were prospectively enrolled and their plasma levels of soluble lectin-like oxidized LDL receptor-1 (sLOX-1), high-sensitivity C-reactive protein (hs-CRP), and high-sensitivity troponin T (hs-TnT) were measured. Another set of 20 patients with stable angina pectoris (SAP) without plaque rupture or erosion served as controls. Among 128 ACS patients, 75 patients underwent OCT procedure to evaluate culprit plaque morphology, and were categorized into two groups; ACS with plaque rupture (ruptured ACS; R-ACS, n=54) and ACS without plaque rupture (non-ruptured ACS; N-ACS, n=21). RESULTS: Levels of sLOX-1 (p<0.001), hs-CRP (p=0.048) and hs-TnT (p<0.001) were significantly higher in R-ACS than SAP. Levels of sLOX-1 were also significantly higher in R-ACS than in N-ACS (p<0.001); whereas levels of hs-CRP (p=0.675), as well as those of hs-TnT (p=0.055), were comparable between R-ACS and N-ACS. Comparison of receiver operating characteristic (ROC) curves among sLOX-1, hs-CRP and hs-TnT to differentiate R-ACS from N-ACS revealed that the area under the curve (AUC) values of sLOX-1, hs-CRP and hs-TnT were 0.782, 0.531 and 0.643, respectively. ROC curves, generated for these biomarkers, to differentiate ACS with thin-cap fibroatheroma (TCFA) from those without demonstrated that the AUC values of sLOX-1, hs-CRP and hs-TnT were 0.718, 0.506 and 0.524, respectively. CONCLUSION: sLOX-1, but not hs-CRP or hs-TnT, can differentiate ACS with plaque rupture from those without, and ACS with TCFA from those without.

Lectin-like oxidized low-density lipoprotein receptor 1 signal is a potent biomarker and therapeutic target for human rheumatoid arthritis.

OBJECTIVE: To determine whether lectin-like oxidized low-density lipoprotein (ox-LDL) receptor 1 (LOX-1) and the soluble form of LOX-1 (sLOX-1) are novel target molecules for the diagnosis and treatment of rheumatoid arthritis (RA). METHODS: Expression of ox-LDL and LOX-1 proteins in human RA synovium was evaluated by immunohistochemistry. Human RA fibroblast-like synoviocytes (FLS) were assessed for ox-LDL-induced expression of LOX-1 and ox-LDL-induced production of matrix metalloproteinase 1 (MMP-1) and MMP-3. Levels of sLOX-1 in the plasma and synovial fluid of patients with RA, compared with patients with osteoarthritis (OA), were determined by a specific chemiluminescence enzyme-linked immunoassay. In animal experiments, ox-LDL was injected into the knee joints of mice, with or without an anti-LOX-1 neutralizing antibody or sLOX-1, and the severity of arthritis was analyzed by histology and immunohistochemistry. RESULTS: Oxidized LDL and LOX-1 proteins were detected in the RA synovial tissue. Levels of MMP-1 and MMP-3 were enhanced by stimulation of RA FLS with ox-LDL, and the production of both MMPs was inhibited by blockade of the ox-LDL-LOX-1 interaction with the anti-LOX-1 neutralizing antibody or sLOX-1. Levels of sLOX-1 in the plasma and synovial fluid of RA patients were significantly higher than those in OA patients and healthy controls and were positively correlated with inflammation markers and the extent of RA disease activity. In the knees of mice, blockade of the ox-LDL-LOX-1 interaction suppressed arthritic changes and reduced the expression of MMP-3 induced by ox-LDL. CONCLUSION: These findings strongly indicate that sLOX-1 is a novel biomarker that may be useful for the diagnosis of RA and for the evaluation of disease activity in RA. Furthermore, the results suggest that LOX-1 may be a potent therapeutic target for RA.

MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice.

BACKGROUND: Cholesterol efflux from cells to apolipoprotein A-I (apoA-I) acceptors via the ATP-binding cassette transporters ABCA1 and ABCG1 is thought to be central in the antiatherogenic mechanism. MicroRNA (miR)-33 is known to target ABCA1 and ABCG1 in vivo. METHODS AND RESULTS: We assessed the impact of the genetic loss of miR-33 in a mouse model of atherosclerosis. MiR-33 and apoE double-knockout mice (miR-33(-/-)Apoe(-/-)) showed an increase in circulating HDL-C levels with enhanced cholesterol efflux capacity compared with miR-33(+/+)Apoe(-/-) mice. Peritoneal macrophages from miR-33(-/-)Apoe(-/-) mice showed enhanced cholesterol efflux to apoA-I and HDL-C compared with miR-33(+/+)Apoe(-/-) macrophages. Consistent with these results, miR-33(-/-)Apoe(-/-) mice showed reductions in plaque size and lipid content. To elucidate the roles of miR-33 in blood cells, bone marrow transplantation was performed in these mice. Mice transplanted with miR-33(-/-)Apoe(-/-) bone marrow showed a significant reduction in lipid content in atherosclerotic plaque compared with mice transplanted with miR-33(+/+)Apoe(-/-) bone marrow, without an elevation of HDL-C. Some of the validated targets of miR-33 such as RIP140 (NRIP1) and CROT were upregulated in miR-33(-/-)Apoe(-/-) mice compared with miR-33(+/+)Apoe(-/-) mice, whereas CPT1a and AMPKα were not. CONCLUSIONS: These data demonstrate that miR-33 deficiency serves to raise HDL-C, increase cholesterol efflux from macrophages via ABCA1 and ABCG1, and prevent the progression of atherosclerosis. Many genes are altered in miR-33-deficient mice, and detailed experiments are required to establish miR-33 targeting therapy in humans.

Matrix metalloproteinase-9 for the earliest stage acute coronary syndrome.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is regarded as a biomarker of plaque rupture or vulnerability and is elevated in patients with acute coronary syndrome (ACS). The aim of the present study was to evaluate the diagnostic value of MMP-9 for early ACS (≤4h of onset) and late ACS (>4h after onset), compared with high-sensitivity troponin T (hs-TnT). METHODS AND RESULTS: MMP-9 and hs-TnT were measured in 200 patients with ST elevation ACS (STEACS; 115 early STEACS and 85 late STEACS patients), and 66 patients with non-ST elevation ACS (NSTEACS; 25 early NSTEACS and 41 late NSTEACS patients). Forty patients with stable angina pectoris (SAP) were enrolled as a control group. MMP-9 levels were significantly higher in patients with early STEACS (P<0.001), early NSTEACS (P<0.001), late STEACS (P<0.001) and late NSTEACS (P=0.025) than SAP. MMP-9 levels were significantly higher in patients with early STEACS (P=0.017) and early NSTEACS (P=0.034) than late STEACS and late NSTEACS, respectively. Levels of hs-TnT were significantly lower in patients with early STEACS (P<0.001) and early NSTEACS (P=0.007) than late STEACS and late NSTEACS, respectively. On receiver operating characteristic curve analysis, area under the curve of early STEACS, early NSTEACS, late STEACS and late NSTEACS was 0.880, 0.782, 0.790 and 0.648 for MMP-9, and 0.707, 0.725, 0.993 and 0.920 for hs-TnT, respectively. CONCLUSIONS: MMP-9 levels were elevated earlier than hs-TnT and had a higher diagnostic value for early ACS, but not for late ACS, reflecting plaque rupture or vulnerability.

Soluble lectin-like oxidized LDL receptor-1 and high-sensitivity troponin T as diagnostic biomarkers for acute coronary syndrome. Improved values with combination usage in emergency rooms.

BACKGROUND: Although highly sensitive assays for troponin T (hs-TnT) have been developed, the sensitivity and specificity of hs-TnT for diagnosing acute coronary syndrome (ACS) remains imperfect. We evaluated the diagnostic value of a new biomarker of plaque vulnerability (soluble lectin-like oxidized low-density lipoprotein receptor-1, sLOX-1) as compared with hs-TnT in the emergency room (ER). METHODS AND RESULTS: Plasma sLOX-1 and serum hs-TnT levels were measured in 200 consecutive patients presenting with chest symptoms and ECG abnormalities in the ER (116 ST elevation ACS [STEACS], 44 non-ST elevation ACS [NSTEACS], 40 non-ACS). The non-ACS group consisted of patients with cardiovascular diseases such as coronary spastic angina pectoris, pulmonary thromboembolism, perimyocarditis and takotsubo cardiomyopathy. Levels of sLOX-1 and hs-TnT were significantly higher in STEACS and NSTEACS than in non-ACS patients. The receiver-operating characteristic (ROC) curves of sLOX-1 and hs-TnT for detecting ACS, using the non-ACS patients as negative references, showed that the area under the curve (AUC) values of sLOX-1 and hs-TnT were 0.769 and 0.739, respectively. In the lower hs-TnT (<0.0205ng/ml) subgroup, the AUC value of the ROC curve of sLOX-1 for detecting ACS was 0.869. CONCLUSIONS: The diagnostic value for ACS was comparable between sLOX-1 and hs-TnT, and the accuracy of ACS diagnosis appeared to improve when sLOX-1 and hs-TnT were measured in combination.

Pentraxin 3 as a biomarker for acute coronary syndrome: comparison with biomarkers for cardiac damage.

BACKGROUND: Pentraxin 3 (PTX3) is increased in circulating blood during the acute stage of acute coronary syndrome (ACS). Therefore, we compared diagnostic values of PTX3 for ACS with those of biomarkers for myocardial damage, such as troponin T (TnT) and heart-type fatty acid binding protein (H-FABP). METHODS AND RESULTS: Patients (n = 87) undergoing coronary angiography (CAG), consisting of 16 ACS and 71 non-ACS patients were enrolled. Non-ACS consists of 12 patients with normal CAG, 30 stable angina pectoris (SAP) patients controlled by medical treatment, and 29 SAP patients who required elective coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft). Age, gender, or prevalence of diabetes, hypertension, or smoking was not significantly different between ACS and non-ACS groups. Serum total, high-density lipoprotein, or low-density lipoprotein cholesterol, or triglyceride levels were not significantly different between ACS and non-ACS. PTX3 levels were not significantly correlated with lipid profiles or different between those with and without conventional risk factors. Circulating PTX3, TnT, and H-FABP levels were significantly higher in ACS than non-ACS. In receiver-operating characteristic (ROC) curves, area under the curve (AUC) values for PTX3, TnT and H-FABP were 0.920, 0.674, and 0.690, respectively. ROC curves of PTX3 (AUC: 0.901), TnT (AUC: 0.731), and H-FABP (AUC: 0.633) for ST-elevation ACS were similar to those for whole ACS. In a TnT-negative subgroup, the AUC values of PTX3 and H-FABP for ACS were 0.981 and 0.489, respectively. CONCLUSIONS: PTX3 is a sensitive and specific biomarker for the diagnosis of ACS, and shows additional diagnostic values when measured in combination with TnT.

SR-PSOX/CXCL16 plays a critical role in the progression of colonic inflammation.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is initiated and perpetuated by a dysregulated immune response to unknown environmental antigens such as luminal bacteria in genetically susceptible hosts. SR-PSOX/CXCL16, a scavenger receptor that binds phosphatidylserine and oxidised lipoprotein, has both phagocytic activity and chemotactic properties. The aim of this study was to investigate the role of SR-PSOX/CXCL16 in patients with IBD and experimental murine colitis. METHODS: The serum levels of SR-PSOX/CXCL16 were measured in patients with IBD. The roles of SR-PSOX/CXCL16 in phagocytosis of bacterial components and cytokine production by macrophages from wild-type (WT) and SR-PSOX/CXCL16 knockout (KO) mice were assessed. Colitis was induced by administering dextran sulfate sodium (DSS) to WT and SR-PSOX/CXCL16 KO mice. Colonic inflammation was analysed by clinical, histological and immunological parameters. Finally, the effect of a monoclonal antibody (mAb) to SR-PSOX/CXCL16 on DSS-induced colitis and trinitrobenzene sulfonic acid-induced colitis models was evaluated. RESULTS: Serum levels of SR-PSOX/CXCL16 correlated significantly with the disease activity of patients with IBD. Ex vivo experiments showed that SR-PSOX/CXCL16 was involved in both phagocytosis of bacterial antigens and the T helper 1 immune response through the production of interleukin 12 and interferon γ. In vivo murine experiments demonstrated the upregulated gene expression of SR-PSOX/CXCL16 in inflamed colonic tissues and the predominant expression of SR-PSOX/CXCL16 on macrophages. SR-PSOX/CXCL16 KO mice were less susceptible to colonic inflammation than were their WT littermates. Administration of SR-PSOX/CXCL16 mAb ameliorated the condition in the two different experimental colitis models. CONCLUSIONS: SR-PSOX/CXCL16 plays a critical role in colonic inflammation and could be a potential therapeutic target for patients with IBD.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 as an early biomarker for ST elevation myocardial infarction: time-dependent comparison with other biomarkers: time-dependent comparison with other biomarkers.

BACKGROUND: The diagnostic sensitivity of myocardial necrosis markers, such as creatine kinase-MB (CK-MB), cardiac troponins, myoglobin and heart-type fatty acid-binding protein (H-FABP) for the earliest stage of ST-elevation myocardial infarction (STEMI), remains insufficient. We compared a new biomarker of plaque vulnerability (soluble lectin-like oxidized low-density lipoprotein receptor-1, sLOX-1) with other biomarkers at the earliest stage of STEMI. METHODS AND RESULTS: Plasma sLOX-1 levels were measured in 125 STEMI, 44 non-STEMI (NSTEMI) and 125 non-acute myocardial infarction (non-AMI) patients and were significantly (P < 0.0001) higher in the STEMI and NSTEMI than in the non-AMI patients (median, 25th and 75th percentiles: 241.0, 132.3 and 472.2 vs. 147.3, 92.9 and 262.4 vs. 64.3, 54.4 and 84.3 pg/ml, respectively). At the optimal cut-off value of 91.0 pg/ml, sLOX-1 discriminated STEMI from non-AMI with 89.6% sensitivity and 82.4% specificity. Time-dependent changes in sLOX-1, H-FABP, myoglobin, troponin T and CK-MB were analyzed in 27 STEMI patients. Elevated plasma sLOX-1 levels persisted for 24h after admission, whereas other markers were not elevated at the time of admission and peaked at ≥ 2h thereafter. The diagnostic sensitivity of sLOX-1, H-FABP, myoglobin, troponin T and CK-MB for STEMI upon admission (89 min after onset) was 93%, 78%, 70%, 56% and 33%, respectively. CONCLUSIONS: Plasma sLOX-1 diagnosed the early stages of STEMI more accurately than H-FABP, myoglobin, troponin T and CK-MB.