Zhong-Hai Wei

Diabetes-Induced Oxidative Stress in Endothelial Progenitor Cells May Be Sustained by a Positive Feedback Loop Involving High Mobility Group Box-1.

Oxidative stress is considered to be a critical factor in diabetes-induced endothelial progenitor cell (EPC) dysfunction, although the underlying mechanisms are not fully understood. In this study, we investigated the role of high mobility group box-1 (HMGB-1) in diabetes-induced oxidative stress. HMGB-1 was upregulated in both serum and bone marrow-derived monocytes from diabetic mice compared with control mice. In vitro, advanced glycation end productions (AGEs) induced, expression of HMGB-1 in EPCs and in cell culture supernatants in a dose-dependent manner. However, inhibition of oxidative stress with N-acetylcysteine (NAC) partially inhibited the induction of HMGB-1 induced by AGEs. Furthermore, p66shc expression in EPCs induced by AGEs was abrogated by incubation with glycyrrhizin (Gly), while increased superoxide dismutase (SOD) activity in cell culture supernatants was observed in the Gly treated group. Thus, HMGB-1 may play an important role in diabetes-induced oxidative stress in EPCs via a positive feedback loop involving the AGE/reactive oxygen species/HMGB-1 pathway.

Advanced glycation endproducts impair endothelial progenitor cell migration and homing via syndecan 4 shedding

Endothelial progenitor cells (EPCs) are a subtype of bone marrow–derived progenitor cells. Stromal cell‐derived factor 1 (SDF‐1)‐mediated EPC mobilization from bone marrow to areas of ischemia plays an important role in angiogenesis. Previous studies have reported that advanced glycation endproducts (AGEs), which are important mediators of diabetes‐related vascular pathology, may impair EPC migration and homing, but the mechanism is unclear. Syndecan‐4 (synd4) is a ubiquitous heparan sulfate proteoglycan receptor on the cell surface, involved in SDF‐1‐dependent cell migration. The extracellular domain of synd4 (ext‐synd4) is shed in the context of acute inflammation, but the shedding of ext‐synd4 in response to AGEs is undefined. Here we investigated changes in ext‐synd4 on EPCs in response to AGEs, focusing on the influence of impaired synd4 signaling on EPC migration and homing. We found decreased full length and increased residue of synd4 in cells incubated with AGEs, with concomitant increase in the soluble fragment of ext‐synd4 in the cell medium. EPCs from patients with type 2 diabetes expressed less ext‐synd4 as assessed by Western blotting. Flow cytometry analysis showed less ext‐synd4 on circulating CD34+ peripheral blood mononuclear cells, of which EPCs form a subgroup. We then explored the role of synd4 in EPC migration and homing. Impaired migration of synd4‐deficient EPCs was observed by a 2D‐chemotaxis slide. Furthermore, poor homing of synd4−/− EPCs was observed in a mouse model of lower limb ischemia. This study demonstrates that the shedding of synd4 from EPCs plays a key role in AGE‐mediated dysfunction of EPC migration and homing. Stem Cells 2017;35:522–531

Therapeutic effect of rotational atherectomy with implantation of drug eluting stent in heavily coronary calcified patients

Background Rotational atherectomy (RA) could facilitate the percutaneous coronary intervention (PCI) in heavily coronary calcified patients. The effectiveness and safety of this technique needs to be further evaluated. Methods & Results Eighty patients who underwent RA in our center from September 2011 to June 2014 were enrolled. The mean age was 72.4 ± 10.4 years. The left ventricular ejection fraction (LVEF) was average 52.3% ± 8.48% and the estimated glomerular filtration rate was 73.2 ± 3.20 mL/min per 1.73 m2. The coronary lesions were complex, with Syntax score 29.5 ± 9.86. The diameter of reference vessel was 3.4 ± 0.45 mm and the average diameter stenosis of target vessels was 80% ± 10%. All the patients were deployed with drug eluting stents (DES) successfully after RA. The patients were followed up for 12–18 months. Kaplan-Meier plots estimated the survival rate was 93.4% and the cumulative incidence of major adverse cardiac and cerebral events (MACCE) was 25.4%. Bleeding and procedural-related complications were quite low. COX proportional hazards model for multivariate analysis demonstrated that diabetes, LVEF and maximum pressure of postdilatation were the predictors of MACCE. Conclusions RA followed by implantation of DES was effective and safe for heavily coronary calcified patients. Diabetes, LVEF and maximum pressure of postdilatation were predictive for MACCE.

A meta-analysis for efficacy and safety evaluation of transcatheter left atrial appendage occlusion in patients with nonvalvular atrial fibrillation.

Objectives: This meta-analysis was conducted to evaluate the efficacy and safety of transcatheter left atrial appendage (LAA) occlusion in patients with nonvalvular atrial fibrillation. Methods: The randomized controlled trials (RCT) or observational studies with any transcatheter LAA occlusion devices were searched in PubMed, Embase, and Cochrane library from inception to November 2015. The incidence rates from individual studies were combined to evaluate the procedural efficacy and safety, including all-cause death, cardiac/neurological death, stroke, transient ischemic attack (TIA), thrombosis, hemorrhagic complications, and pericardial effusion/tamponade. Results: Thirty-eight studies involving 3585 patients and 6 different occlusion devices were eligible for our inclusion criteria. The procedural failure rate for LAA closure was 0.02 (95% CI: 0.02–0.03). The all-cause mortality was 0.03 (95% CI: 0.02–0.03) and cardiac/neurological mortality was 0 (95% CI: 0.00–0.01). The stroke/TIA rate was estimated only 0.01 (95% CI: 0.01–0.01). The incidence of thrombus on devices was 0.01 (95% CI: 0.01–0.02). The major hemorrhagic complication rate was estimated 0.01 (95% CI: 0.00–0.01). Pericardial effusion/tamponade was estimated 0.02 (95% CI: 0.02–0.03). No heterogeneity was observed for above pooled estimates (I 2 = 0). In devices subgroups analysis, the all-cause mortality and cardiac/neurological mortality of PLAATO group were the highest (P = 0.01 and P < 0.01 respectively), whereas the incidence of thrombus on devices in the ACP group was the highest (P < 0.01). In follow-up period subgroups analysis, there were significant differences in all-cause death, stroke/TIA, major hemorrhage, and pericardial effusion/tamponade events between the shorter and longer follow-up period subgroups (P < 0.05). However, the differences among the subgroups were numerically small. Conclusions: the pooled data demonstrated that transcatheter LAA occlusion was effective and safe in the patients with nonvalvular atrial fibrillation who were not suitable for lifelong antithrombotic therapy.

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

High mobility group box-1 (HMGB-1), a typical damage-associated molecular pattern protein released from various cells, was first identified in 1973. It is usually stored in the nuclei of cells. Several modifications of HMGB-1 promote its translocation to the cytosol, and it is actively or passively released from cells. When outside of the cells, HMGB-1is crucial in inflammation. It exerts its biological functions via interaction with its receptors, including receptor for advanced glycation end products (RAGE) and Toll-like receptor 4(TLR4). A large number of studies showed a close link between inflammation and thrombosis. This review demonstrated the increased expression of HMGB-1 in thrombosis-related diseases, including coronary artery disease, stroke, peripheral arterial disease, disseminated intravascular coagulation, and venous thrombosis. Besides, it summarized the current understanding of the emerging link between HMGB-1 and thrombosis from three aspects: platelet, NETs, and coagulation and fibrinolysis factors. Finally, it explored the possible therapeutic strategies targeting HMGB-1 for treating thrombosis-related diseases.

High Mobility Group B-1 (HMGB-1) Promotes Apoptosis of Macrophage-Derived Foam Cells by Inducing Endoplasmic Reticulum Stress

Background/Aims: High mobility group B-1 (HMGB-1)-induced endoplasmic reticulum stress (ERS) has been implicated in inflammation and dendritic cell maturation. C/EBP-homologous protein (CHOP) is a vital component of ERS and apoptosis and plays a critical role in atherosclerosis. However, only a little information is available about the role of HMGB-1 in foam cell formation. Thus, the role of HMGB-1-induced ERS/CHOP pathway in apoptosis and formation of macrophage-derived foam cells is investigated. Methods: RAW264.7 cells were treated with oxidized low-density lipoprotein (oxLDL) in the absence and/or presence of HMGB-1, N-acetylcysteine (NAC, an antioxidant), glycyrrhizin (Gly, an HMGB-1 inhibitor), tunicamycin (TM, an ERS inducer), and 4-phenylbutyrate (4-PBA, an ERS inhibitor). Reactive oxygen species (ROS) production was examined by dihydroethidium (DHE) staining. Oil Red O staining, intracellular total cholesterol assay, and Dil-oxLDL uptake assay evaluated the accumulation of lipids in macrophages. Cell apoptosis was measured by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Western blot detected the expression of HMGB-1/ERS/CHOP pathway. Results: oxLDL induced HMGB-1 translocation and secretion in a dose- and time-dependent manner, which was inhibited by NAC. oxLDL-induced lipid accumulation in macrophages was promoted synergistically by HMGB-1 that was attenuated by Gly. Moreover, TM synergized with oxLDL induced lipid accumulation and apoptosis of macrophages; however, 4-PBA alleviated the oxLDL-induced apoptotic foam cells. Additionally, the inhibition of ERS with 4-PBA suppressed the expression of HMGB-1-induced CHOP. Conclusions: OxLDL triggered HMGB-1 secretion in macrophages via oxidative stress. Furthermore, HMGB-1 promoted the formation and apoptosis of macrophage-derived foam cells via activation of ERS/CHOP pathway.

The value of shock index in prediction of cardiogenic shock developed during primary percutaneous coronary intervention

BackgroundShock index(SI) is a conventional predictive marker for haemodynamic state. Its breakpoint varies by different conditions according to previous studies. The current study was performed to evaluate the capability of SI in prediction of cardiogenic shock(CS) developed during primary percutaneous coronary intervention (pPCI).MethodsTotal 870 patients of ST segment elevation myocardial infarction(STEMI) who were haemodynamic stable before pPCI were involved in the study. In this cohort, 625 consecutive patients composed analysis series and 245 consecutive patients composed validation series. Multivariate regression analysis was used to evaluate whether SI was a significant predictor of developed CS and Hosmer-Lemeshow test was used to assess the goodness of model fitness. Receiver-operating characteristics (ROC) analysis was used to compare the predictive capability of SI with other predictors. The sensitivity, specificity, accuracy, positive and negative predictive values of SI at different cutoff values was compared to identify a best breakpoint.ResultsIn the analysis series, SI and Killips classification were identified as independent predictors. ROC analysis demonstrated the diagnostic capability of SI was superior to pre-procedural systolic blood pressure(SBP) or heart rate(HR) alone (0.8113 vs 0.7582, P = 0.04 and 0.8113 vs 0.7111, P < 0.001). The diagnostic capability of SI was equivalent to that of combination of SBP, HR and Killips claasification(0.8133 vs 0.8137, P = 0.97). SI had a high specificity and low sensitivity. When the cutoff value was set at 0.93, the positive predictive value, negative predictive value and diagnostic accuracy was 42.6%, 95.1% and 87.4% respectively. In validation series, the area under ROC curve was 0.8245, which was similar to that in the analysis series. The positive predictive value, negative predictive value and diagnostic accuracy at the cutoff value of 0.93 was 53.8%, 93.2% and 88.9% respectively.ConclusionsSI has a high predictive accuracy for developing CS during pPCI in STEMI patients. It is an excellent exclusion diagnosis index rather than confirmative diagnosis index.

Therapeutic effect of interventional therapy for unprotected left main coronary artery lesions in aged patients.

Objective To assesse the therapeutic effect of interventional therapy in aged patients with unprotected left main coronary artery (UPLM) lesions. Methods A total of 61 patients who were over 60 years and accepted interventional therapy of UPLM from January 2012 to November 2013 in our hospital were followed up for average 14.6 months by telephone call or outpatient visits. We analyzed the clinical features data of the interventional therapy and assessed the factors that likely influenced the clinical prognosis. Results The average age of the 61 patients was 73.9 years. The average left ventricular ejection fraction (LVEF) was 47.7%. The median of the estimated glomerular filtration rate (eGFR) was 52 mL/min per 1.73 mm2. The average SYNTAX score was 27.4 and the median of stent length was 36 mm. The cumulative incidence of cardiac death at 30 days and major adverse cardiac events (MACE) after one year was 6.6% and 32.5% estimated by Kaplan-Meier plots respectively. No severe hemorrhagic complications were observed during follow-up period. On multivariate regression analysis with a COX proportional hazards model, LVEF was an independent predictor of cardiac death at 30 days [Hazard ratio (HR): 0.7, P = 0.01]. As for MACE after one year, LVEF and eGFR were both independent predictors (HR: 0.91, P = 0.06 for LVEF, HR: 0.03, P = 0.097 for eGFR). Conclusions The interventional therapy for UPLM was effective and safe in aged patients. LVEF was the only predictor of cardiac death at 30 days, while LVEF and eGFR were both independent predictors of MACE after one year.