Zulong Xie

Ginsenoside Rb3 protects cardiomyocytes against ischemia-reperfusion injury via the inhibition of JNK-mediated NF-κB pathway: a mouse cardiomyocyte model.

Ginsenoside Rb3 is extracted from the plant Panax ginseng and plays important roles in cardiovascular diseases, including myocardial ischemia-reperfusion (I/R) injury. NF-κB is an important transcription factor involved in I/R injury. However, the underlying mechanism of ginsenoside Rb3 in myocardial I/R injury remains poorly understood. In the current study, a model of myocardial I/R injury was induced via oxygen and glucose deprivation (OGD) followed by reperfusion (OGD-Rep) in mouse cardiac myoblast H9c2 cells. Our data demonstrate that ginsenoside Rb3 suppresses OGD-Rep-induced cell apoptosis by the suppression of ROS generation. By detecting the NF-κB signaling pathway, we discover that the protective effect of ginsenoside Rb3 on the OGD-Rep injury is closely related to the inhibition of NF-κB activity. Ginsenoside Rb3 inhibits the upregulation of phospho-IκB-α and nuclear translocation of NF-κB subunit p65 which are induced by ORD-Rep injury. In addition, the extract also inhibits the OGD-Rep-induced increase in the expression of inflammation-related factors, such as IL-6, TNF-α, monocyte chemotactic protein-1 (MCP-1), MMP-2 and MMP-9. However, LPS treatment alleviates the protective roles of ginsenoside Rb3 and activates the NF-κB pathway. Finally, the upstream factors of NF-κB were analyzed, including the Akt/Foxo3a and MAPK signaling pathways. We find that ginsenoside Rb3 pretreatment only decreases the phosphorylation of JNK induced by OGD-Rep injury, an indicator of the MAPK pathway. Importantly, an inhibitor of phospho-JNK, SP600125, protects against OGD-Rep induced apoptosis and inhibited NF-κB signaling pathway, similar to the roles of ginsenoside Rb3. Taken together, our results demonstrate that the protective effect of ginsenoside Rb3 on the OGD-Rep injury is attributed to the inhibition of JNK-mediated NF-κB activation, suggesting that ginsenoside Rb3 has the potential to serve as a novel therapeutic agent for myocardial I/R injury.

Patterns of coronary plaque progression: phasic versus gradual. A combined optical coherence tomography and intravascular ultrasound study.

ObjectiveSome plaques grow slowly in a linear manner, whereas others undergo a rapid phasic progression. However, the detailed in-vivo relationship between plaque characteristics and plaque progression pattern has not been reported. The current study aimed to investigate the plaque progression patterns with serial intravascular ultrasound (IVUS) examinations, and to correlate baseline plaque characteristics assessed by optical coherence tomography and IVUS with plaque progression patterns. MethodsA total of 248 coronary lesions from 157 patients were identified and imaged by both optical coherence tomography and IVUS at baseline. IVUS examination was repeated at 6 and 12 months. Plaque progression was defined as greater than or equal to 5% increase in percent atheroma volume by IVUS. The progression patterns were divided into three groups: no progression, rapid phasic progression, and gradual progression. ResultsAmong 248 lesions, 190 (77%) showed no progression. Among 58 lesions with progression, 20 (34%) showed gradual progression, whereas 38 (66%) showed rapid phasic progression. Multivariate analysis indicated that thin-cap fibroatheroma [odds ratio (OR)=5.24, 95% confidence interval (CI) 2.04–13.4; P=0.001], microvessel (OR=2.20, 95% CI 1.10–4.79; P=0.045), and positive remodeling (OR=2.64, 95% CI 1.19–5.81; P=0.016) were associated independently with rapid phasic progression. ConclusionThree-quarters of coronary plaques did not progress over time with contemporary medical treatment. Among the lesions with progression, one-third showed a gradual pattern and two-thirds showed a rapid phasic pattern. The presence of thin-cap fibroatheroma, microvessel, and positive remodeling were the independent predictors for rapid phasic pattern progression of coronary atherosclerotic plaques.

Comparison of optical coherence tomography and intravascular ultrasound for evaluation of coronary lipid-rich atherosclerotic plaque progression and regression.

AIMS Compared with intravascular ultrasound (IVUS), optical coherence tomography (OCT) has relative merits and demerits for detecting plaque characteristics. It remains unknown whether the IVUS and OCT evaluations of plaque progression/regression are consistent. We sought to analyse the correlations between IVUS and OCT evaluations of plaques at single time points, and compare temporal changes in the IVUS and OCT data. METHODS AND RESULTS Eighty-eight lipid-rich plaques from 65 patients with coronary artery disease were analysed with IVUS and OCT at baseline and 12-month follow-up. Fibrous cap thickness on OCT was negatively correlated with total atheroma volume on IVUS (r = -0.28, P = 0.009), but not with percent atheroma volume (P = 0.84). Changes on OCT were not significantly correlated with changes on IVUS. Plaques that showed progression, regression, or no change on IVUS showed no differences in terms of changes in the OCT parameters fibrous cap thickness (P = 0.199), maximum lipid core arc (P = 0.755), mean lipid core arc (P = 0.936), and lipid index (P = 0.91). The incidence of thin-cap fibroatheroma (TCFA) was similar among the above three plaque groups at baseline (P = 0.79) and follow-up (P = 0.609). CONCLUSION Although fibrous cap thickness on OCT was negatively correlated with plaque size on IVUS at single time points, changes in OCT parameters were not correlated with changes in IVUS measures over time. Lesion progression/regression on IVUS was not associated with changes in OCT parameters (fibrous cap thickness, lipid core arc, lipid index, and TCFA).

MicroRNA-182 prevents vascular smooth muscle cell dedifferentiation via FGF9/PDGFRβ signaling

The abnormal phenotypic transformation of vascular smooth muscle cells (SMCs) causes various proliferative vascular diseases. MicroRNAs (miRNAs or miRs) have been established to play important roles in SMC biology and phenotypic modulation. This study revealed that the expression of miR-182 was markedly altered during rat vascular SMC phenotypic transformation in vitro. We aimed to investigate the role of miR-182 in the vascular SMC phenotypic switch and to determine the potential molecular mechanisms involved. The expression of miR-182 gene was significantly downregulated in cultured SMCs during dedifferentiation from a contractile to a synthetic phenotype. Conversely, the upregulation of miR-182 increased the expression of SMC-specific contractile genes, such as α-smooth muscle actin, smooth muscle 22α and calponin. Additionally, miR-182 overexpression potently inhibited SMC proliferation and migration under both basal conditions and under platelet-derived growth factor-BB stimulation. Furthermore, we identified fibroblast growth factor 9 (FGF9) as the target gene of miR-182 for the phenotypic modulation of SMCs mediated through platelet-derived growth factor receptor β (PDGFRβ) signaling. These data suggest that miR-182 may be a novel SMC phenotypic marker and a modulator that may be used to prevent SMC dedifferentiation via FGF9/PDGFRβ signaling.

Relation between baseline plaque features and subsequent coronary artery remodeling determined by optical coherence tomography and intravascular ultrasound

Atherosclerosis often leads to myocardial infarction and stroke. We examined the influence of baseline plaque characteristics on subsequent vascular remodeling in response to changes in plaque size. Using optical coherence tomography (OCT) and intravascular ultrasound (IVUS), we examined 213 plaques from 138 patients with acute coronary syndrome at baseline and repeated IVUS at the 12-month follow-up. The change in external elastic membrane (EEM) area for each 1 mm2 change in plaque area (i.e., the slope of the regression line) was calculated as a measure of vascular remodeling capacity. In plaques with static positive remodeling, the slope was smaller than in plaques without static positive remodeling. In addition, the slope of the regression line for lesions with a large plaque burden was much smaller than that for lesions with a small plaque burden. Multivariate linear regression analysis showed that diabetes, calcification and static positive remodeling were inversely and independently associated with the level of change in EEM area/change in plaque area. Lesions with a large plaque burden, calcifications or static positive remodeling had less remodeling capacity, and calcification and static positive remodeling were independent predictors of reduced subsequent remodeling. Therefore, calcifications and static positive remodeling could be used as morphological biomarkers to predict decreased subsequent arterial remodeling.

Geraniin protects bone marrow‑derived mesenchymal stem cells against hydrogen peroxide‑induced cellular oxidative stress in vitro

Administration of bone marrow-derived mesenchymal stem cells (MSCs) has emerged as a potential therapeutic approach for the treatment of myocardial infarction (MI). However, the increase in reactive oxygen species (ROS) in ischemic cardiac tissue compromises the survival of transplanted MSCs, thus resulting in limited therapeutic efficiency. Therefore, strategies that attenuate oxidative stress-induced damage and enhance MSC viability are required. Geraniin has been reported to possess potent antioxidative activity and exert protective effects on numerous cell types under certain conditions. Therefore, geraniin may be considered a potential drug used to modulate MSC-based therapy for MI. In the present study, MSCs were pretreated with geraniin for 24 h and were exposed to hydrogen peroxide (H2O2) for 4 h. Cell apoptosis, intracellular ROS levels and mitochondrial membrane potential were measured using Annexin V-fluorescein isothiocyanate/ propidium iodide staining, the 2′,7′-dichlorodihydrofluorescein diacetate fluorescent probe and the membrane permeable dye JC-1, respectively. Glutathione and malondialdehyde levels were also investigated. The expression levels of apoptosis-associated proteins and proteins of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway were analyzed by western blotting. The results demonstrated that geraniin could significantly attenuate H2O2-induced cell damage by promoting MSC survival, reducing cellular ROS production and maintaining mitochondrial function. Furthermore, geraniin modulated the expression levels of phosphorylated-Akt in a time- and dose-dependent manner. The cytoprotective effects of geraniin were suppressed by LY294002, a specific PI3K inhibitor. In conclusion, the present study revealed that geraniin protects MSCs from H2O2-induced oxidative stress injury via the PI3K/Akt pathway. These findings indicated that cotreatment of MSCs with geraniin may optimize therapeutic efficacy for the clinical treatment of MI.

Relationship between serum angiopoietin-like protein 2 and plaque vulnerability in patients with coronary artery disease and diabetes

AIMS Obesity is characterized by low-grade inflammation state and excessive inflammatory cytokine production of adipose tissue. Angiopoietin-like protein 2 (ANGPTL2), a novel proinflammatory adipokine, has recently been suggested to be involved in the pathogenesis of atherosclerosis in animal studies. However, no data regarding the relationship between ANGPTL2 and morphologic characteristics of coronary plaques in humans are available. The aim of the current study was to investigate the in vivo association between serum ANGPTL2 level and plaque vulnerability in patients with coronary artery disease (CAD) and diabetes. METHODS AND RESULTS 72 consecutive patients with clinically proven CAD and diabetes were enrolled between October 2013 and December 2014. Circulating ANGPTL2 concentration was measured using a human ANGPTL2 sandwich enzyme-linked immunosorbent assay (ELISA) kit. The morphologic characteristics of non-culprit lipid-rich plaques were assessed by optical coherence tomography. Fibrous cap thickness was significantly and negatively correlated with serum ANGPTL2 levels (r = -0.29, P = 0.005). A significant and positive correlation was observed between mean lipid core arc and serum ANGPTL2 concentration (r = 0.32, P = 0.01). In addition, levels of serum ANGPTL2 were significantly higher in patients with thin-cap fibroatheroma (TCFA) than those without TCFA (P < 0.001). Multivariate logistic regression analysis showed that a higher serum ANGPTL2 concentration was a powerful predictor of TCFA (odds ratio: 3.18, P = 0.002). CONCLUSION Serum ANGPTL2 level is significantly associated with plaque vulnerability in patients with CAD and diabetes. Systemic ANGPTL2 comprises an inflammatory adipokine that links the adipose tissue and coronary plaque.

IN-STENT LIPID-RICH PLAQUE IN HIGH CHOLESTEROL DIET RABBIT VALIDATED BY INTRAVASCULAR OPTICAL COHERENCE TOMOGRAPHY AND HISTOLOGY

Objectives In-stent lipid-rich plaque had been found frequently in patients underwent stent implantation by optical coherence tomography (OCT) and intravascular ultrasound (IVUS). The paucity of a reliable animal model limits the further research of lipid-rich plaque development and treatment. The present study aims to develop an animal model of lipid-rich plaque. Methods Four New Zealand White Rabbits were fed a high cholesterol diet (HCD) until euthanasia. Eight bare metal stents were randomly implanted into iliac arteries after 1 week HCD. The rabbits underwent OCT and IVUS imaging at 8 weeks after stent implantation. Then the stents were harvested and processed for light microscopy. On OCT imaging, in-stent lipid-rich plaques were identified by diffusely bordered, signal-poor regions. In-stent plaques were defined as peri-strut fomay macrophage clusters with or without calcification, fibroatheroma, and ruptures with thrombosis in in-stent neointima. Results All stents underwent OCT and histology examination. With OCT, total 127cross-sections and 962 struts were analysed. The 99.75% struts were covered well at 8 weeks after implantation. In-stent lipid-rich plaques with diffusely bordered, signal-poor regions were identified in 23.40% of cross-sections and 87.50% of stents. The histology examination of corresponding images further confirmed the components of in-stent lipid-rich plaque. In-stent lipid-rich plaques were characterised by peri-strut fomay macrophage clusters with lipid-rich necrotic core in in-stent neointima. Conclusions In-stent lipid-rich plaque model was developed successfully in high cholesterol diet rabbit. OCT is a useful tool to detect in-stent lipid-rich plaque features in vivo. The combination of in vivo OCT and the in-stent lipid-rich plaque model may be an important research tool in furthering our understanding and treatment of in-stent plaque in patients underwent stent implantation.