Circulatory soluble LOX-1 is a novel predictor for coronary artery disease patients.

BACKGROUND: This study investigated the biomarker effect of soluble lectin-like oxidised low-density lipoprotein (sLOX-1) levels for the evaluation of stable and unstable coronary heart disease, correlating it with aging. METHODS: This case-control study was conducted at the Cardiology Department of Xiangya Hospital between June 2015 and September 2018. Stable coronary artery disease (CAD) patients were confirmed by an invasive coronary angiogram, and American College of Cardiology as well as European Cardiology Society clinical protocols were used for the diagnosis of unstable CAD subjects. Plasma sLOX-1 levels were determined from 226 stable CAD patients, 138 unstable CAD subjects and 75 healthy participants by enzyme-linked immunosorbent assay. RESULTS: Plasma sLOX-1 expressions were significantly elevated in stable CAD patients (4.5-fold) and unstable CAD patients (5.8-fold) above that of volunteer healthy participants. Moreover, between the stable and unstable patient groups, sLOX-1 concentrations were also statistically significantly different (p < 0.001). Levels of plasma sLOX-1 in the healthy female (30-60 years), and stable and unstable CAD female subjects (61-84 years) were markedly elevated compared with healthy male (30-60 years), as well as stable and unstable CAD male patients (61-84 years) (p < 0.001). Besides, in the female unstable CAD (61-84 years) subjects, circulatory sLOX-1 expressions were much higher than in the younger female unstable CAD (30-60 years) patients (p < 0.001). The stable CAD patients were clearly differentiated from healthy subjects with a high sensitivity of the area under the curve (AUC = 0.895). Unstable CAD patients and healthy subjects were also markedly different with a high sensitivity, as shown by AUC (0.902). Stable and unstable CAD subjects were differentiated with an AUC of 0.867. CONCLUSIONS: Elevated plasma sLOX-1 levels could be regarded as a novel biomarker for detecting CAD patients and there was a significant association with gender and aging.

lncRNA PINK1-AS Aggravates Cerebral Ischemia/Reperfusion Oxidative Stress Injury through Regulating ATF2 by Sponging miR-203.

Ischemic stroke is a common disease that led to high mortality and high disability. NADPH oxidase 2- (NOX2-) mediated oxidative stress and long noncoding RNA have important roles in cerebral ischemia/reperfusion (CI/R) injury, whereas whether there is interplay between them remains to be clarified. This study was performed to observe the role of lncRNA PINK1-antisense RNA (PINK1-AS) in NOX2 expression regulation. An in vivo rat model (MCAO) and an in vitro cell model (H/R: hypoxia/reoxygenation) were utilized for CI/R oxidative stress injury investigation. The expression levels of lncRNA PINK1-AS, activating transcription factor 2 (ATF2), NOX2, and caspase-3 and the production level of ROS and cell apoptosis were significantly increased in CI/R injury model rats or in H/R-induced SH-SY5Y cells, but miR-203 was significantly downregulated. There was positive correlation between PINK1-AS expression level and ROS production level. PINK1-AS and ATF2 were found to be putative targets of miR-203. Knockdown of lncRNA PINK1-AS or ATF2 or the overexpression of miR-203 significantly reduced oxidative stress injury via inhibition of NOX2. Overexpression of lncRNA PINK1 significantly led to oxidative stress injury in SH-SY5Y cells through downregulating miR-203 and upregulating ATF2 and NOX2. lncRNA PINK1-AS and ATF2 were the targets of miR-203, and the lncRNA PINK1-AS/miR-203/ATF2/NOX2 axis plays pivotal roles in CI/R injury. Therefore, lncRNA PINK1-AS is a possible target for CR/I injury therapy by sponging miR-203.

Overexpression of miR-126 Protects Hypoxic-Reoxygenation-Exposed HUVEC Cellular Injury through Regulating LRP6 Expression.

The aim of the study was to explore the clinical impact of circulatory miR-126 as a candidate for novel biomarker in patients with coronary artery disease (CAD) and its protective role against hypoxia/reoxygenation- (H/R-) exposed HUVEC cellular injury. A total of 278 subjects, which included 153 subjects with angiographically confirmed CAD, 70 unstable angina subjects, and 55 healthy individuals, along with 18-hour HR-induced HUVECs were recruited in this study. Plasma miR-126 levels were significantly downregulated in stable and unstable CAD patients as well as 18-hour HR-exposed HUVECs as compared with controls. Stable and unstable CAD subjects were significantly differentiated from healthy individuals with a predictive value of AUC 0.903 and 0.923, respectively. Moreover, peripheral circulatory miR-126 expressions in elderly (71-90 years) stable and unstable CAD patients were comparatively lower than younger (30-50 years) subjects. The caspase-3 activity, intracellular ROS concentrations, and cellular viabilities were evidently increased in 18-hour HR-exposed HUVECs than in normal cells (P < 0.001). On the contrary, mimic expressions of miR-126 prominently reduced caspase-3 activity and intracellular ROS levels and markedly enhanced HUVEC cellular viabilities (P < 0.001). LRP6 expressions were significantly elevated in HR-induced HUVECs, whereas overexpression of miR-126 remarkably decreased LRP6 expressions (P < 0.001). Plasma miR-126 could be used as a novel biomarker for early prediction of CAD subjects. Overexpression of miR-126 significantly improved HUVEC cellular viabilities by downregulation of LRP6 protein expression, suggesting a potential therapeutic target for CAD patients.

Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 acts as a new biomarker for NSTEMI and STEMI patients.

Objective: The diagnostic significance of plasma soluble lectin-like oxidized low-density lipoprotein receptor-1(sLOX-1) for non-ST segment elevated myocardial infarction (NSTEMI) and ST segment elevated myocardial infarction (STEMI) were explored by this study. Methods: In this study, 107 acute NSTEMI, 223 acute STEMI and 107 healthy subjects, and hypoxic (1%02) ventricular cardiomyocytes H9c2 were used. Results: The significantly up-regulated plasma sLOX-1 levels in acute NSTEMI and STEMI patients compared to healthy subjects (p<0.001). Both male and female NSTEMI and STEMI groups had remarkably higher concentrations of plasma sLOX-1 levels than controls (p<0.001). The circulating levels of sLOX-1 expression obviously elevated in elderly aging (60-75 years) than younger aging (30-45 years) both male and female in healthy subjects as well as NSTEMI and STEMI (p<0.001). Altered levels of sLOX-1 in blood plasma revealed a significant discrimination with high sensitivity and specificity between healthy with NSTEMI and STEMI subjects with AUC= 0.916 and AUC= 0.925 respectively. Moreover, LOX-1 levls were highly released from 6hour, 12hour and 18hour hypoxic injured H9c2 cells than normoxic cell (p<0.001), reflected circulating plasma sLOX-1 in AMI patients. Conclusion: Elevated levels of plasma sLOX-1concentrations might be used as a clinical biomarker for early recognition of NSTEMI and STEMI patients. Multicenter larger scale studies are necessary before use in clinical practice.

Role of Plasma Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 and microRNA-98 in Severity and Risk of Coronary Artery Disease.

BACKGROUND: Coronary artery diseases are the most important cause of premature death, and these diseases are predominantly related to atherosclerosis. Soluble lectin-like oxidized low-density lipoprotein receptor-1 and microRNAs are closely associated with atherosclerotic coronary heart diseases. AIMS: To investigate the relationship between the severity and risk of coronary artery disease and plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 and miR-98. STUDY DESIGN: Case-control study. METHODS: Angiographically documented patients with 38 single-vessel, 75 double-vessel, and 62 multi-vessel coronary artery disease; 62 healthy control participants; and 24-hour hypoxic (1% oxygen) human umbilical vein endothelial cells were included in this study. Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 concentrations were determined through enzyme-linked immunosorbent assays, and miR-98 expressions were measured by quantitative real-time polymerase chain reaction. RESULTS: The expressions of plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels were progressively and significantly higher in patients with single-vessel, double-vessel, and multi-vessel coronary artery disease than in healthy controls (p<0.001). Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 concentrations in female patients with multi-vessel, double-vessel, and single-vessel coronary artery disease had evidently elevated compared with that in male patients (p<0.001). Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels were remarkably increased in females with coronary artery disease in different age groups compared with the males in the same age groups (p<0.001). Patients with single-vessel (areas under the curve=0.879), double-vessel (area under the curve=0.928), and multi-vessel (area under the curve=0.943) coronary artery disease have been clearly differentiated from healthy participants with respect to high sensitivity and specificity. The expression of miR-98 was noticeably downregulated in patients with single-, double- and multi-vessel occluded coronary artery disease and in hypoxic human umbilical vein endothelial cell compared with controls (p<0.001). Significantly elevated lectin-like oxidized low-density lipoprotein receptor-1 and caspase-3 activity and remarkably decreased cellular viability in hypoxic injured human umbilical vein endothelial cell. On the contrary, mimic of miR-98 markedly reduced caspase-3 and lectin-like oxidized low-density lipoprotein receptor-1 levels and highly increased cellular viability. CONCLUSION: Elevated circulating plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels have a potential impact to identify the severity of coronary artery disease and have a strong correlation with aging as well as the female gender. Reduced plasma miR-98 level is possibly considered a risk factor for coronary artery disease, and agomiR-98 prevents atherosclerosis and cellular injury by targeting lectin-like oxidized low-density lipoprotein receptor-1.

Retinol binding protein 4 promotes hyperinsulinism­induced proliferation of rat aortic smooth muscle cells.

Recent studies have suggested that retinol binding protein 4 (RBP4), an adipocytokine related to insulin resistance (IR), may play an important role in the development of atherosclerosis and cardiovascular diseases (CVD). Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is one of the most common causes of atherosclerosis. Hyperinsulinism promotes proliferation of VSMCs through the MAPK pathway. However, whether RBP4 is involved in insulin-induced proliferation of VSMCs leading to atherosclerosis remains unclear. In the present study, we evaluated the role of RBP4 and the potential relevance of signaling pathways in this process. Different concentrations of RBP4 (1 and 4 µg/ml) were added to rat aortic smooth muscle cells (RASMCs) during insulin-induced proliferation. The levels of cell growth signaling pathway proteins ERK1/2, p-ERK1/2, JAK2, p-JAK2, STAT3 and p-STAT3 were assessed by western blotting in order to identify the pathway(s) that are activated during insulin-induced proliferation. The specific inhibitors of ERK1/2 (PD98059) and JAK2 (AG490) were used to confirm our findings. Insulin induced proliferation of RASMCs in a concentration- and time-dependent manner, and increased the expression of ERK1/2, p-ERK1/2, JAK2, p-JAK2, STAT3 and p-STAT3 in a time-dependent manner. RBP4 enhanced insulin-induced proliferation of RASMCs and expression of p-ERK1/2 and p-JAK2. RBP4­induced proliferation of RASMCs was reduced by the ERK1/2 inhibitor, while it was unaffected by the JAK2 inhibitor. These results suggest that RBP4 mediates VSMC proliferation induced by insulin via activation of the MAPK pathway, and highlight RBP4 as a modulator of atherosclerosis in hyperinsulinemia, therby enhancing our understanding on a number of unexpected aspects of CVD.