Inhibition of circ_0000231 suppresses oxidized low density lipoprotein-induced apoptosis, autophagy and inflammation in human umbilical vein endothelial cells by regulating miR-590-5p/PDCD4 axis.

BACKGROUND: Circular RNAs (circRNAs) are the emerging informative RNAs, involved in cardiovascular diseases including atherosclerosis (AS). Endothelial injury is the initial qualitative change of AS. Thus, the objective of this study was to confirm the dysregulation and mechanism of circ_0000231 in cell model of AS at early stage in human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (ox-LDL). METHODS: The expression of circ_0000231, miR-590-5p and programmed cell death 4 (PDCD4) was detected using real-time quantitative PCR and western blot. Cell injury was measured with MTT, flow cytometry, caspase-3 activity assay and enzyme-linked immunosorbent assay (ELISA). The interaction among circ_0000231, miR-590-5p and PDCD4 was validated by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) and pull-down assays. RESULTS: Stress ox-LDL decreased cell viability, and increased apoptosis rate and caspase-3 activity in HUVECs in a dose- and time-dependent manner in concomitant with promotions of interleukin-6, interleukin-1ß, tumor necrosis factor-α, LC3-II/I and Beclin-1 levels. Besides, circ_0000231 and PDCD4 expressions were upregulated, and miR-590-5p was downregulated in ox-LDL-stimulated HUVECs. Functionally, knockdown of circ_0000231 and overexpression of miR-590-5p could suppress ox-LDL-elicited above effects on apoptosis, autophagy and inflammatory response, accompanied with PDCD4 downregulation. Physically, miR-590-5p could directly interact with circ_0000231 and PDCD4. CONCLUSION: Downregulation of circ_0000231 suppresses HUVECs from ox-LDL-induced injury partially through regulating miR-590-5p/PDCD4 axis via competing endogenous RNA mechanism, showing a novel potential target for the pathology and treatment of endothelial injury in AS.

The Association of Syntax Score with Levels of Lipoprotein(a) and Inflammatory Biomarkers in Patients with Stable Coronary Artery Disease and Different Low-Density Lipoprotein Cholesterol Levels.

INTRODUCTION: Lipoprotein(a) (Lp(a)) is associated with the severity of coronary lesions evaluated using Syntax score in patients with stable coronary artery disease (CAD). However, the effect of low-density lipoprotein cholesterol (LDL-C) levels on the association of Lp(a) levels with Syntax score remains unclear. METHODS: A total of 646 patients with stable CAD were enrolled in the present study. Lp(a) levels were measured with an AU5800 Chemistry Analyzer. Syntax scores were calculated by two advanced interventional cardiologists. SPSS 22.0 was used for statistical analyses. RESULTS: The concentration of Lp(a) ranged from 1 to 192 mg/dL. Pearson's correlation analysis showed a positive correlation between Syntax score and the level of Lp(a) (r = 0.108, p = 0.006). The LDL-C ≥100 mg/dL group presented with a higher Lp(a) level, 16 (9-29) vs 13 (7-24). Pearson's correlation analysis identified a correlation between Lp(a) level and Syntax score (r = 0.249, p < 0.001) only in the LDL-C ≥100 mg/dL group. Multivariate logistic regression analysis revealed the positive predictive value of an Lp(a) level >30 mg/dL for a Syntax score ≥23 only in the LDL-C ≥100 mg/dL group, adjusted odds ratio 2.895, p = 0.010. A receiver operating characteristic curve analysis confirmed the predictive value of Lp(a) levels for a Syntax score ≥23 in the LDL-C ≥100 mg/dL group with a cutoff value for Lp(a) >30 mg/dL. DISCUSSION: The association between Lp(a) level and Syntax score was only maintained in the LDL-C ≥100 mg/dL group. An Lp(a) level >30 mg/dL was an independent predictor of a Syntax score ≥23 only in the LDL-C ≥100 mg/dL group. The effect of LDL-C levels on the association of Lp(a) levels with Syntax score requires further investigations.

Sex-specific association of monocyte count to high-density lipoprotein ratio with SYNTAX score in patients with suspected stable coronary artery disease.

Recently, the monocyte count to high-density lipoprotein cholesterol ratio (MHR) was found to be associated with the SYNTAX score in patients with both stable coronary artery disease (CAD) and acute coronary syndrome (ACS). The MHR was significantly higher in male patients. However, the sex-specific association of MHR with SYNTAX score in stable CAD was not well explored. Thus, the present study aimed to investigate the association of MHR and presence and severity of CAD evaluated by coronary angiography and the SYNTAX score in males and females.In total, 873 patients who received selective coronary angiography between March 2017 and July 2018 were included in the present study. Patients were divided into 3 groups according to MHR tertiles. The MHR was calculated by dividing the monocyte count by the high-density lipoprotein cholesterol level. CAD was defined as at least 50% diameter stenosis of a major coronary artery, including the right coronary, left main coronary, left anterior descending, and left circumflex arteries. The SYNTAX score was calculated by 2 experienced interventional cardiologists. SYNTAX score ≥23 was defined as a high SYNTAX score.Males showed a significantly higher MHR (12.2 [8.9-15.5] vs 9.3 [6.2-12.1], P < .001), accompanied by a higher prevalence of CAD (68.1% vs 53.4%, P < .001). Male sex remained an independent predictor of elevated MHR after correction for confounding factors (adjusted odds ratio [OR] 3.102, P = .001). The association between MHR and SYNTAX score was confirmed only in male stable patients with CAD (r = 0.113, P = .036). Multivariate logistic regression analysis showed that MHR was an independent predictor of SYNTAX score ≥23 only in male patients with CAD. The receiver-operating characteristic curve showed a predictive value of MHR for high SYNTAX score only in males.A higher MHR in males and a positive correlation of MHR with SYNTAX score were observed only in male stable patients with CAD. Such an easily obtained index may help interventional cardiologists detect high-risk patients before coronary catheterization, but its application may be restricted to males.

A replication study and a meta-analysis of the association between the CDKN2A rs1333049 polymorphism and coronary heart disease.

AIM: The aim of this study was to assess whether rs1333049 was associated with coronary heart disease (CHD) in Han Chinese. METHODS: This case-control study was involved with 599 CHD patients and 591 non-CHD controls. Meanwhile, a comprehensive meta-analysis was also conducted to establish the contribution of rs1333049 to CHD. RESULTS: Our results showed that rs1333049 increased the risk of CHD by 38% (OR=1.38, 95% CI=1.18-1.62). A breakdown analysis by gender further indicated that rs1333049 increased the risk of CHD in men by 29% (OR=1.29, 95% CI=1.05-1.58) and in women by 64% (OR=1.64, 95% CI=1.25-2.16). A follow-up subgroup analysis by age showed there was a significant association between rs1333049 and CHD in women younger than 65 (≤55 years: p=0.001, 55-65 years: p=0.008) and in men aged between 55 and 65 years (p=0.005). Our meta-analysis was involved with 21 studies (25 stages) among 20969 cases and 34114 controls. Our results showed that rs1333049 led to a significantly increased risk of CHD (OR=1.30, 95% CI=1.21-1.39). Further subgroup analyses by ethnicity showed rs1333049 increased the CHD risk by 30% in Europeans (OR=1.30, 95% CI=1.16-1.47) and 27% in Asians (OR=1.27, 95% CI=1.22-1.33). CONCLUSIONS: Our case-control study and meta-analysis suggest that rs1333049 is a useful risk marker of CHD.

Effects of Ca2+-activated potassium and inward rectifier potassium channel on the differentiation of endothelial progenitor cells from human peripheral blood.

Endothelial progenitor cells (EPCs) are bone marrow-derived cells that have the propensity to differentiate into mature endothelial cells (ECs). The transplantation of EPCs has been shown to enhance in vivo postnatal neo-vasculogenesis, as well as repair infarcted myocardium. Via the whole-cell patch clamp technique, numerous types of ion channels have been detected in EPCs, including the inward rectifier potassium channel (IKir), Ca2+-activated potassium channel (IKCa), and volume-sensitive chloride channel, but their influence on the differentiation of EPCs has yet to be characterized. The present study was designed to investigate: (1) which ion channels have the most significant impact on the differentiation of EPCs; (2) what role ion channels play in the functional development of EPCs; (3) the mRNA and protein expression levels of related ion channel subunits in EPCs. In our study, EPCs were obtained from the peripheral blood of healthy adults and cultured with endothelial growth factors. When EPCs differentiate into mature ECs, they lose expression of the stem cell/progenitor marker CD133, as analyzed by flow cytometry (0.44±0.20 %). However, treatment with the potassium channel inhibitor, tetraethylammonium (TEA) results in an increase in CD133+ cells (25.50±7.55 %). In a functional experiment, we observed a reduction in the capacity of TEA treated ECs (differentiated from EPCs) to form capillary tubes when seeded in Matrigel. At the mRNA and protein levels, we revealed several K+ subtypes, including KCNN4 for IKCa, KCNNMA1 for BKCa and Kir3.4 for IKir. These results demonstrate for the first time that potassium channels play a significant role in the differentiation of EPCs. Moreover, inhibition of potassium channels may depress the differentiation of EPCs and the significant potassium channel subunits in EPCs appear to be IKCa, BKCa and Kir3.4.