SCH772984 ameliorates lipopolysaccharide-induced hypoglycemia in mice through reversing MEK/ERK/Foxo1-mediated gluconeogenesis suppression.

Lipopolysaccharide (LPS) results in a lethal hypoglycemic response. However, the main molecular mechanism involved in LPS-induced glucose metabolism disorder is poorly understood. This study intends to investigate the signaling pathways involved in LPS-induced hypoglycemia and potential efficacy of extracellular signal-regulated kinase (ERK) inhibitor SCH772984. The effects of LPS and SCH772984 on gluconeogenesis, glucose absorption, and glycogenolysis were evaluated by pyruvate tolerance test, oral glucose tolerance test, and glucagon test, respectively. After a single intraperitoneal injection of 0.5 mg/kg LPS, the mice's blood glucose levels and gluconeogenesis ability were significantly lower than that of control group. Besides, mRNA and protein expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) decreased significantly after LPS treatment. LPS induced the phosphorylation of ERK1/2, MEK1/2 (mitogen-activated protein kinase), and Foxo1 while inhibited Foxo1 expression in the nucleus, indicating an important role of the MEK/ERK/Foxo1 signaling in the inhibition of gluconeogenesis by LPS. Furthermore, SCH772984 elevated blood glucose, increased the G6Pase and PEPCK expression, and inhibited pERK1/2 and pFoxo1 expression in LPS-induced mice. In summary, LPS inhibited gluconeogenesis and induced hypoglycemia through the MEK/ERK/Foxo1 signal pathway, and ERK inhibitor could effectively reverse decreased blood glucose in mice with LPS treatment. These findings provide a novel therapeutic target for LPS-induced hypoglycemia.

Molecular Mechanism of Berberine in the Treatment of Calcified Aortic Valve Disease Based on AGE-RAGE Signal Pathway.

Objective: We aimed to explore the molecular mechanism of berberine in the treatment of calcified aortic valve disease through the network pharmacology-molecular docking method. Methods: The targets of berberine and calcified aortic valve disease were retrieved, the interactions between the targets were analyzed, Cytoscape software was used to build a "target-path" network, R language was used to conduct enrichment analysis of GO and KEGG pathways, and AutoDock Vina was used to verify the binding force of the target protein and small molecules. Results: 96 targets for berberine and 4293 disease targets were screened through multiple databases, and 56 targets were identified through veen analysis. The enrichment of PPI, GO, and KEGG pathways suggests that berberine may act on PIK3CD, PIK3CB, PIK3R1, MAPK14, MAPK10, and other targets, and regulate the role of calcified aortic valve disease through AGE-RAGE signaling pathway, Chemokine signaling pathway, Lipid and atherosclerosis, and other pathways. The docking results showed that berberine has good binding activity with the target on the key pathway AGE-RAGE signaling pathway. Conclusion: The network pharmacology preliminarily revealed the mechanism of berberine in the treatment of calcified aortic valve disease by regulating vascular calcification, inflammatory reaction, oxidative stress, and other effects, providing the basis for follow-up experimental research, and also providing the basis for clinical medication.

Anatomic predictor of severe prosthesis malposition following transcatheter aortic valve replacement with self- expandable Venus-A Valve among pure aortic regurgitation: A multicenter retrospective study.

Background: Transcatheter aortic valve replacement (TAVR) in the treatment of patients with pure native aortic valve regurgitation (NAVR) has been based on the "off-label" indications, while the absence of aortic valve calcification and difficulty in anchoring was found to significantly increase the risk of prosthesis malposition. The aim of this study was to explore the anatomical predictors of severe prosthesis malposition following TAVR with the self-expandable Venus-A Valve among patients with NAVR. Methods: A total of 62 patients with NAVR who underwent TAVR with Venus-A Valve at four Chinese clinical centers were retrospectively observed. The clinical features, aortic multidetector computed tomography (MDCT) data, and clinical outcomes were compared between non-/mild malposition and severe malposition groups. Univariate logistic regression analysis was used to identify the risk factors of severe prosthesis malposition, and the receiver operating characteristic (ROC) curve was used to explore the predictive value of the risk factors. Results: Valve migration to ascending aortic direction occurred in 1 patient, and the remaining 61 patients (including 19 severe malposition cases and 42 non-/mild malposition cases) were included in the analysis. The diameter and height of the sinotubular junction (STJ) and STJ cover index (STJCI, calculated as 100%*STJ diameter/nominal prosthesis crown diameter) were all greater in the severe malposition group (all p < 0.05). Logistic regression showed that STJ diameter (OR = 1.23, 95% CI 1.04-1.47, p = 0.017), STJ height (OR = 1.24, 95% CI 1.04-1.47, p = 0.017), and STJCI (OR = 1.08, 95% CI 1.01-1.16, p = 0.032) were potential predictors for severe prosthesis malposition. The area under the ROC curve was 0.72 (95% CI 0.58-0.85, p = 0.008) for STJ diameter, 0.70 (95% CI 0.55-0.86, p = 0.012) for STJ height, and 0.69 (95% CI 0.55-0.83, p = 0.017) for STJCI, respectively. The cutoff value was 33.2 mm for STJ diameter (sensitivity was 84.2% and specificity was 65.8%), 24.1 mm for STJ height (sensitivity was 57.9% and specificity was 87.8%), and 81.0% for STJCI (sensitivity was 68.4% and specificity was 68.3%), respectively. Conclusion: Larger and higher STJ, as well as greater STJ to valve crown diameter ratio, may help identify patients at high risk for severe prosthesis malposition among patients with NAVR undergoing TAVR with Venus-A prosthesis valve.

Effect of social app-assisted education and support on glucose control in patients with coronary heart disease and diabetes mellitus.

Background: Social app-assisted education and support may facilitate diabetes self-management. We aim to evaluate the effect of WeChat, a popular social app, on glycemic control in patients with coronary heart disease (CHD) and diabetes mellitus (DM). Methods: We conducted a parallel-group, open-label, randomized clinical trial that included 160 patients with both CHD and diabetes mellitus from a tertiary hospital in China. The intervention group (n = 80) received educational materials (information on glucose monitoring, drug usage, medication, and lifestyle) and reminders in response to individual blood glucose values via WeChat. The control group (n = 80) received usual care. The primary outcome was a change in glycated hemoglobin (HbA1C) levels over 3 months. Secondary outcomes included fasting blood glucose (FBG), systolic blood pressure, and low-density lipoprotein (LDL) cholesterol from baseline to 3 months. Analysis was conducted using a linear mixed model. Results: The intervention group had a greater reduction in HbA1C (-0.85 vs. 0.15%, between-group difference: -1.00%; 95% CI -1.31 to -0.69%; p < 0.001) compared with the control group. Change in fasting blood glucose was larger in the intervention group (-1.53 mmol/L; 95% CI -1.90 to -1.17; p < 0.001) and systolic blood pressure (-9.06 mmHg; 95% CI -12.38 to -5.73; p < 0.001), but not LDL (between-group difference, -0.08 mmol/L; 95% CI -0.22 to 0.05; p = 0.227). Conclusion: The combination of social app with education and support resulted in better glycemic control in patients with CHD and DM. These results suggest that education and support interaction via social app may benefit self-management in CHD and DM.

Risk factors for incomplete thrombosis in false lumen in sub-acute type B aortic dissection post-TEVAR.

There is scarce information about the risk factors for incomplete false lumen thrombosis (FLT) among type B aortic dissection (AD) patients, particularly in the sub-acute phase following thoracic endovascular aortic repair (TEVAR). We enrolled consecutive sub-acute type B AD patients at Xinqiao Hospital (Chongqing, China) from May 2010 to December 2019. Patients with severe heart failure, cancer, and myocardial infarction were excluded. The postoperative computed tomography angiography (CTA) data were extracted from the most recent follow-up aortic CTA. Multivariate logistic regressions were applied to identify the association between FLT and clinical or imaging factors. Fifty-five subjects were enrolled in our study. Twelve participants showed complete FLT, and 2 of these died during the follow-up, while 8 patients died in incomplete FLT group. In the multivariate analysis, maximum abdominal aorta diameter (OR 1.20, 95% CI 1.016-1.417 p = 0.032) and the number of branches arising from the false lumen (FL) (OR 15.062, 95% 1.681-134.982 p = 0.015) were significantly associated with incomplete FLT. The C-statistics was 0.873 (95% CI 0.773-0.972) for the model. The FL diameter (p < 0.001) was significantly shorter following TEVAR, while the true lumen diameter (p < 0.001) and maximum abdominal aorta diameter (p = 0.011) were larger after the aortic repair. There were 21.8% of sub-acute type B AD patients presented complete FLT post-TEVAR. Maximum abdominal aorta diameter and the number of branches arising from the FL were independent risk factors for incomplete FLT. The true lumen diameter, maximum abdominal aorta diameter, and FL diameter changed notably following TEVAR.

Atorvastatin rescues pulmonary artery hypertension via inhibiting the AKT/ERK-dependent PDGF-BB/HIF-1α axis.

BACKGROUND: To explore the role of Atorvastatin in rescuing pulmonary artery hypertension (PAH) via inhibiting the AKT/ERK-dependent PDGF-BB/HIF-1α axis. METHODS: PAH model in rats was established by MCT induction, followed by Atorvastatin intervention. Pulmonary hemodynamic measurement and pulmonary morphological evaluation in rats were conducted. Human pulmonary artery smooth muscle cells (hPASMCs) were subjected to hypoxic exposure or PDGF-BB treatment, followed by Atorvastatin induction. Relative levels of HIF-1α, p-ERK and p-Akt were detected. Viability and apoptosis were respectively determined by cell counting kit-8 (CCK-8) assay and flow cytometry. RESULTS: Atorvastatin protected PAH-induced increases in RVSP and Fulton's index in rats. Meanwhile, it inhibited vascular remodeling following PAH by downregulating HIF-1α and PDGF-BB. Hypoxia or PDGF-BB treatment in hPASMCs resulted in upregulation of p-ERK and p-Akt, and viability increase, which were partially abolished by Atorvastatin intervention. In addition, Atorvastatin triggered apoptosis in hypoxia or PDGF-BB-induced hPASMCs. CONCLUSIONS: Atorvastatin inhibits the activation of HIF-1α and proliferative ability, and triggers apoptosis in hPASMCs exposed to hypoxia or PDGF-BB treatment through inactivating the AKT/ERK pathway.

Incidence, Risk Factors, and Outcomes of Coronary Obstruction Following Valve-in-Valve Transcatheter Aortic Valve Replacement.

There is scant information about the incidence, risk factors, and outcomes of coronary obstruction (CO) following valve-in-valve transcatheter aortic valve replacement (VIV-TAVR). A meta-analysis of the published studies from January 2000 to April 2020 was conducted, and the endpoint was CO. A total of 2858 patients were enrolled in this study. The mean age was 77.7 ± 9.8, and 39.9% of them were female. The Society of Thoracic Surgeons (STS) score, European System for Cardiac Operative Risk Evaluation (EuroSCORE), and Logistic EuroSCORE were 8.9 ± 7.8, 16.0 ± 10.9, and 26.3 ± 16.3, respectively. The overall incidence of CO was 2.58%. CO incidence between patients with prior stented and stentless valves were significantly different (1.67% versus 7.17%), with an odds ratio (OR) of 0.25 and a 95% confidence interval (CI) of 0.14-0.44 (P < 0.00001). The first-generation valves were significantly associated with higher CO incidence compared with the second-generation valves (7.09% versus 2.03%; OR, 2.44; 95%CI, 1.06-5.62; P = 0.04), while no statistical difference was found between self-expandable valves and balloon-expandable valves (2.45% versus 2.60%; OR, 0.99; 95%CI, 0.55-1.79; P = 0.98). Virtual transcatheter to coronary ostia (VTC) distance (3.3 ± 2.1 mm, n = 29 versus 5.8 ± 2.4 mm, n = 169; mean difference, -2.70; 95%CI, -3.46 to -1.95; P < 0.00001) and the sinus of Valsalva (SOV) diameter (27.5 ± 3.8 mm, n = 23 versus 32.3 ± 4.0 mm, n = 101; mean difference, -3.80; 95%CI, -6.55 to -1.05; P = 0.007) were enormously shorter in patients with CO. The 24-hour, in-hospital, and 30-day mortality of patients with CO were 10.5%, 30.8%, and 37.1%, respectively. In conclusion, device selections, VTC distances, and SOV diameters may be important factors in assessing the CO risk in VIV-TAVR.

Downregulation of miR-542-3p promotes osteogenic transition of vascular smooth muscle cells in the aging rat by targeting BMP7.

BACKGROUND: Aging is believed to have a close association with cardiovascular diseases, resulting in various pathological alterations in blood vessels, including vascular cell phenotypic shifts. In aging vessels, the microRNA(miRNA)-mediated mechanism regulating the vascular smooth muscle cell (VSMC) phenotype remains unclarified. MiRNA microarray was used to compare the expressions of miRNAs in VSMCs from old rats (oVSMCs) and young rats (yVSMCs). Quantitative reverse transcription real-time PCR (qRT-PCR) and small RNA transfection were used to explore the miR-542-3p expression in oVSMCs and yVSMCs in vitro. Calcification induction of yVSMCs was conducted by the treatment of ß-glycerophosphate (ß-GP). Alizarin red staining was used to detect calcium deposition. Western blot and qRT-PCR were used to investigate the expression of the smooth muscle markers, smooth muscle 22α (SM22α) and calponin, and the osteogenic markers, osteopontin (OPN), and runt-related transcription factor 2 (Runx2). Lentivirus was used to overexpress miR-542-3p and bone morphogenetic protein 7 (BMP7) in yVMSCs. Luciferase reporter assay was conducted to identify the target of miR-542-3p. RESULTS: Compared with yVSMCs, 28 downregulated and 34 upregulated miRNAs were identified in oVSMCs. It was confirmed by qRT-PCR that oVSMC expressed four times lower miR-542-3p than yVSMCs. Overexpressing miR-542-3p in yVSMCs suppressed the osteogenic differentiation induced by ß-GP. Moreover, miR-542-3p targets BMP7 and overexpressing BMP7 in miR-542-3p-expressing yVSMCs reverses miR-542-3p's inhibition of osteogenic differentiation. CONCLUSIONS: miR-542-3p regulates osteogenic differentiation of VSMCs through targeting BMP7, suggesting that the downregulation of miR-542-3p in oVSMCs plays a crucial role in osteogenic transition in the aging rat.

Association Between Single Nucleotide Polymorphisms in PPARA and EPAS1 Genes and High-Altitude Appetite Loss in Chinese Young Men.

Appetite loss is a common symptom that occurs in high altitude (HA) for lowlanders. Previous studies indicated that hypoxia is the initiating vital factor of HA appetite loss. PPARA, EPAS1, EGLN1, HIF1A, HIF1AN, and NFE2L2 play important roles in hypoxic responses. We aimed to explore the association of these hypoxia-related gene polymorphisms with HA appetite loss. In this study, we enrolled 416 young men who rapidly ascended to Lhasa (3700 m) from Chengdu (<500m) by plane. PPARA, EPAS1, EGLN1, HIF1A, HIF1AN, and NFE2L2 were genotyped by MassARRAY. Appetite scores were measured to identify HA appetite loss. Logistic regression and multiple genetic models were tested to evaluate the association between the single nucleotide polymorphisms (SNPs) and risk of HA appetite loss in crude and adjusted (age and SaO2) analysis. Subsequently, Haploview software was used to analyze the linkage disequilibrium (LD), haplotype construction and the association of diverse haplotypes with the risk of HA appetite loss. Our results revealed that allele "A" in PPARA rs4253747 was significantly associated with the increased risk of HA appetite loss. Codominant, dominant, recessive, and log-additive models of PPARA rs4253747 showed the increased risk of HA appetite loss in the crude and adjusted analysis. However, only dominant, overdominant, and log-additive models of EPAS1 rs6756667 showed decreased risk of HA appetite loss in the crude and adjusted analysis. Moreover, the results from haplotype-based test showed that the rs7292407-rs6520015 haplotype "AC" was associated with HA appetite loss in the crude analysis rather than the adjusted analysis. In this study, we first established the association of SNPs in PPARA (rs4253747) and EPAS1 (rs6756667) genes with susceptibility to HA appetite loss in Han Chinese young men. These findings provide novel insights into understanding the mechanisms involved in HA appetite loss.

Nox4 and soluble epoxide hydrolase synergistically mediate homocysteine-induced inflammation in vascular smooth muscle cells.

BACKGROUND: Hyperhomocysteinemia leads to a vascular smooth muscle cell (VSMC) inflammatory response. Meanwhile, Nox4 dependent reactive oxygen species (ROS) signaling and soluble epoxide hydrolase (sEH)/epoxyeicosatrienoic acids (EETs) are both involved in vascular inflammation. Herein, we hypothesized that Nox4 and soluble epoxide hydrolase cross regulated during homocysteine-induced VSMC inflammation. METHODS AND RESULTS: In cultured VSMCs, the expression of the inflammatory factors VCAM1 and ICAM1 was measured by real-time PCR and Western blotting, while supernatant MCP1 was measured by ELISA. Upon VSMC stimulation with 50 µΜ homocysteine, we observed the VCAM1 and ICAM1 mRNA levels were increased by 1.15 and 1.0 folds, respectively. The MCP1 levels in the supernatant of cultured VSMCs treated with 100 µΜ increased to 1.76 folds. As expected, homocysteine induced Nox4 expression and Nox4-dependent ROS generation. The sEH expression was also upregulated in the presence of homocysteine in a dose-dependent manner. Furthermore, we knocked down Nox4 with siRNA. Knockdown of Nox4 decreased ROS generation and homocysteine-induced sEH expression. Overexpression of Nox4 with an adenovirus stimulated sEH expression. Similarly, knockdown or chemical inhibition of sEH blunted the upregulation of Nox4 by homocysteine. In vivo, in homocysteine-fed mice, concomitant upregulation of Nox4 and sEH was associated with increased VCAM1 and ICAM1 expression in the aortic wall. CONCLUSIONS: The inflammatory response induced by homocysteine in VSMCs was accompanied by Nox4 and sEH upregulation. Nox4 and soluble epoxide hydrolase synergistically contribute to homocysteine-induced inflammation.

Statins may be beneficial for patients with pulmonary hypertension secondary to lung diseases.

BACKGROUND: Previous animal studies and clinical trials report inconsistent findings regarding the role of statins in pulmonary hypertension (PH). Systematic reviews have shown no use of statins on pulmonary arterial hypertension (PAH). This is the first meta-analysis of randomized controlled trials (RCTs) determining the clinical impacts of statin therapy on patients with PH secondary to lung diseases. METHODS: Electronic databases and manual bibliographical searches were conducted. Eligible studies included RCTs of at least 3 months that evaluated statin therapy as compared with control in adult patients with PH due to pulmonary diseases. Statistical analyses were performed to calculate mean difference, relative risks (RRs), and 95% confidence intervals (CIs) using random-effect model. RESULTS: A total of 6 RCTs were identified and included in this study. Five trials reported the effects of statins in patients with both chronic obstructive pulmonary disease (COPD) and PH, and the remaining 1 was based on PH due to pneumoconiosis. We found that statin therapy was associated with increased 6-minute walk distance and reduced pulmonary artery systolic pressure. There was no observed difference in the incidence of death, drug withdrawal, and adverse event between statin and control group. CONCLUSIONS: Our findings suggest that statins might be safe and beneficial for patients with PH due to chronic lung diseases. However, larger RCTs with more patients and longer observational duration are needed.

A simply prepared small-diameter artificial blood vessel that promotes in situ endothelialization.

Synthetic grafts are of limited use in small-diameter vessels (Φ<6mm) due to the poor patency rate. The inability of such grafts to achieve early endothelialization together with the compliance mismatch between the grafts and the native vessels promote thrombosis, which eventually leads to graft occlusion. In the current study, stromal cell-derived factor (SDF)-1α/vascular endothelial growth factor (VEGF)-loaded polyurethane (PU) conduits were simply prepared via electrospinning. The mechanical property, drug release behavior and cytocompatibility of the conduits were investigated. The effects of the conduits on endothelial progenitor cell (EPC) mobilization and differentiation were examined in vitro. Then, the conduits were implanted as canine femoral artery interposition grafts. The results revealed that SDF-1α and VEGF were quickly released shortly after implantation, and the conduits exhibited slow and sustained release thereafter. The cytokines had definite effects on EPC mobilization and differentiation in vitro and promoted conduit endothelialization in vivo. The conduits had good tissue compatibility and favorable compliance. All of these features inhibited the conduits from being occluded, thereby improving their long-term patency rate. At 6th month postoperatively, 5 of the 8 grafts were patent while all the 8 grafts without the cytokines were occluded. These findings provide a simple and effective method for the construction of small-diameter artificial blood vessels with the aim of facilitating early endothelialization and improving long-term patency. STATEMENT OF SIGNIFICANCE: (1) SDF-1α/VEGF loaded PU conduits were simply prepared by electrospinning. The cytokines with definite and potent effects on angiogenesis were used to avoid complicated mechanism researches. Compared with most of the current vascular grafts which are of poor strength or elasticity, the conduits have favorable mechanical property. All of these inhibit the conduits from occlusion, and thus improve their long-term patency rate. (2) For the in vivo tests, the dogs did not receive any anticoagulant medication in the follow-up period to expose the grafts to the strictest conditions. In vivo endothelialization of the conduits was thoroughly investigated by Sonography, HE staining, SEM and LSCM. The study will be helpful for the construction of small-diameter artificial blood vessels.

Improving endothelialization by the combined application of polyethylene glycol coated cerium oxide nanoparticles and VEGF in electrospun polyurethane scaffolds.

Synthetic small-diameter vascular grafts are of limited use mainly due to the lack of endothelial cells (ECs), which inhibit intraluminal thrombosis and intimal hyperplasia. Grafts loaded with homing factors for circulating endothelial progenitor cells (EPCs) have the potential to achieve in situ endothelialization. In view of the important role that EPCs play in the construction of small-diameter artificial blood vessels, antioxidant therapy aiming to inhibit oxidative stress-induced EPC apoptosis should be the focus of clinical interest. In this study, polyethylene glycol coated cerium oxide nanoparticles (CNPs-PEG) with antioxidant properties were successfully synthesized and characterized. The effects of CNPs-PEG on EPC viability and EPC apoptosis induced by oxidative stress were examined. Then, CNPs-PEG together with a potent angiogenesis cytokine vascular endothelial growth factor (VEGF) were encapsulated into polyurethane (PU) scaffolds via electrospinning. The morphology, mechanical properties and CNPs-PEG/VEGF release profiles of the scaffolds were investigated. The growth of EPCs on the scaffolds, and the effects of the released CNPs-PEG and VEGF on anti-EPC apoptosis and endothelialization in vitro were studied. The results showed that CNPs-PEG had favorable stability and cytocompatibility. They could effectively inhibit H2O2-induced EPC apoptosis. The scaffolds showed sustained release behavior of CNPs-PEG/VEGF and favorable cytocompatibility. The released CNPs-PEG retained the anti-apoptosis properties and, moreover, enhanced the effects of VEGF on the mobilization and differentiation of EPCs. It is concluded that the combined application of CNPs-PEG and VEGF in electrospun PU scaffolds facilitated endothelialization in vitro, and thus should be promising for the construction of small-diameter artificial blood vessels.

The ubiquitin-activating enzyme E1 as a novel therapeutic target for the treatment of restenosis.

AIMS: The ubiquitin-activating enzyme E1 (UBA1, E1), the apex of the ubiquitin proteasome pathway, plays a critical role in protein degradation and in pathological processes. Whether UBA1 participates the development of vascular restenosis remains unknown. This study aims to determine the role of UBA1 in the development of balloon injury induced neointimal formation. METHODS AND RESULTS: Immunostaining and western blots were used to examine the expression of the ubiquitinated protein in the injured carotid after angioplasty. Higher levels of ubiquitinated protein were observed in the neointima. Local delivery of potent chemical UBA1 inhibitor PYR-41 (100 µM) and UBA1 shRNA lentivirus both resulted in a substantial decrease in intimal hyperplasia at 2 weeks and 4 weeks after balloon injury. UBA1 inhibition also reduced Ki-67 positive cell percentage and inflammatory response in the carotid artery wall. We further determined that in vitro UBA1 inhibition was able to ameliorate TNF-α-induced nuclear factor-kappa B (NF-κB) activation by reducing IκB degradation in vascular smooth muscle cells (VSMCs). UBA1 inhibition also led to the accumulation of short-lived proteins such as p53, p21 and c-jun, which may account for the UBA1 inhibition-induced cell cycle delay. Thus, VSMCs proliferation was blocked. CONCLUSIONS: UBA1 inhibition effectively suppresses neointimal thickening through its anti-proliferative and anti-inflammatory effects. Our results provide further evidence that the ubiquitin-proteasome system is a potential new target for the prevention of vascular restenosis.

Bivalirudin Anticoagulant Therapy With or Without Platelet Glycoprotein IIb/IIIa Inhibitors During Transcatheter Coronary Interventional Procedures: A Meta-Analysis.

The safety and effectiveness of using the direct thrombin inhibitor bivalirudin during transcatheter coronary interventional procedures remains uncertain.This study aimed to systematically assess anticoagulation with bivalirudin alone or bivalirudin plus glycoprotein (GP) IIb/IIIa inhibitors (bivalirudin-based anticoagulant therapy) in patients undergoing percutaneous coronary intervention (PCI) procedures by a meta-analysis of randomized controlled trials (RCTs).Systematical searches of the MEDLINE, EMBASE, and Cochrane databases were conducted. RCTs comparing bivalirudin-based anticoagulant therapy with a comparable heparin therapy in patients undergoing PCI were eligible. Risk ratios (RRs) with 95% confidence intervals (CIs) served as summary statistics.A total of 38,096 patients from 17 RCTs were randomized to the bivalirudin group (n = 18,878) or heparin group (n = 19,218) in the meta-analysis. No significant differences in death, myocardial infarction or reinfarction, ischemia-driven revascularization, or in-stent thrombosis were observed between the 2 groups (all P > 0.05). Notably, bivalirudin-based therapy showed a highly significant 34% decrease in the incidence of major bleeding (RR = 0.66; 95% CI 0.54-0.81; P < 0.001) and a 28% reduction in the need for blood transfusion (RR = 0.72; 95% CI 0.56-0.91; P < 0.01). Meta-regression analyses demonstrated that additional administration of GP IIb/IIIa receptor inhibitors (P = 0.01), especially eptifibatide (P = 0.001) and tirofiban (P = 0.002), was likely to increase the major bleeding risk associated with bivalirudin.Bivalirudin, in comparison to heparin, is associated with a markedly lower risk of major bleeding, and the additional use of GP IIb/IIIa inhibitors may weaken this benefit.

Down-regulation of mir-542-3p promotes neointimal formation in the aging rat.

AIM: To explore mir-542-3p mediated inhibition of vascular smooth muscle cell (VSMC) proliferation through the inhibition of Syk activation. METHODS AND RESULTS: MicroRNA (mir)-542-3p was selected for analysis based on miRNA microarray and qRT-PCR results. In vitro mir-542-3p expression was significantly downregulated in old (o)VSMCs compared with young (y)VSMCs under serum stimulation conditions. Upregulation of mir-542-3p in oVSMCs significantly inhibited VSMC proliferation, whereas downregulation of mir-542-3p in yVSMCs increased VSMC proliferation. We identified spleen tyrosine kinase (Syk) as a direct target of mir-542-3p by database search, and showed that its expression and phosphorylation were higher in oVSMCs than in yVSMCs after serum stimulation. Luciferase assays confirmed that Syk is a direct target of miR-3542-3p. Knock-down of mir-542-3p in yVSMCs inhibited the activation of the Syk downstream effectors STAT3 and STAT5, whereas mir-542-3p overexpression enhanced STAT3 and STAT5 activities. In a rat balloon injury model, mir-542-3p inhibited neointima formation and proliferating cell nuclear antigen (PCNA) protein expression. CONCLUSION: Mir-542-3p modulates VSMC proliferation via the Syk/STAT3-STAT5 axis. Downregulation of mir-542-3p may explain age-related neointimal hyperplasia in rats.

Tailored antiplatelet therapy and clinical adverse outcomes.

OBJECTIVE: The clinical evidence regarding the influence of tailored antiplatelet strategy on adverse outcomes has been controversial. The aim of the study was to evaluate the significance of tailored antiplatelet therapy with respect to clinical adverse events in antiplatelet-resistant patients. METHODS: Randomised studies that assess clinical relevance of personalised antiplatelet treatment in antiplatelet-resistant patients were identified through a literature search: PubMed, EMBASE, Web of Science and the Cochrane Library. The primary endpoint was the composite of death from any cause and stent thrombosis. All total clinical adverse events and bleeding complications were evaluated. RESULTS: Data were combined across seven randomised studies comprising 12 048 subjects, of whom 3738 (31.0%) were found to be antiplatelet-resistant. Antiplatelet-resistant patients provided with tailored antiplatelet therapy showed less risk of death or stent thrombosis than those assigned conventional antiplatelet treatment (0.5% vs. 2.2%; OR (95% CI) 0.25 (0.13 to 0.49), p<0.0001). A significant benefit in terms of total adverse event risk reduction was observed during follow-up for tailored vs conventional antiplatelet therapy (5.5% vs. 10.0%; OR (95% CI) 0.40 (0.20 to 0.77), p=0.006). No statistical difference in bleeding complications was observed between these two groups (p=0.08). CONCLUSIONS: In the study, personalised antiplatelet treatment for antiplatelet resistance was found to be associated with less occurrence of death or stent thrombosis and the less risk of total clinical adverse events than conventional treatment, without increasing the risk of bleeding complications.

Decreased plasma apolipoprotein A-IV levels in patients with acute coronary syndrome.

PURPOSE: The purpose of this study was to evaluate the relationship between apolipoprotein A-IV (apoA-IV) plasma concentrations and acute coronary syndrome (ACS). METHODS: Plasma apoA-IV concentrations were measured in 115 patients with different types of ACS and in 68 gender- and age-matched control subjects using Enzyme-Linked Immunosorbent Assay (ELISA) kits. The clinical data were collected by an internist, who was blinded to plasma apoA-IV concentrations. RESULTS: Plasma apoA-IV levels in ACS patients were significantly decreased compared to the levels in control subjects (437.0±157.5 µg/mL vs. 590.2±183.7 µg/mL, P<0.001). An statistically significant decreasing trend of plasma apoA-IV levels from the control subjects, to patients with unstable angina pectoris (UAP) (457.3±152.9 µg/mL), to patients with acute myocardial infarction (AMI) (311.7±127.8 µg/mL), was observed. Moreover, plasma apoA-IV level was negatively associated with New York Heart Association (NYHA) functional class. NYHA class II (467.2±142.1 µg/mL, P<0.001) and class III/IV (368.1±170.8 µg/mL, P<0.001) patients had statistically decreased levels of plasma apoA-IV when compared to the control subjects. A stepwise multivariate regression analysis identified types of ACS, NYHA classes, and plasma fibrinogen levels as the most important determinants of plasma apoA-IV levels in ACS patients. CONCLUSIONS: Low plasma apoA-IV levels are associated with ACS, and plasma apoA-IV levels may be a potential treatment target for ACS patients.

Hydrogen-rich medium suppresses the generation of reactive oxygen species, elevates the Bcl-2/Bax ratio and inhibits advanced glycation end product-induced apoptosis.

The purpose of the present study was to determine whether using hydrogen-rich medium (HRM) to increase hydrogen levels in endothelial cells (ECs) protects ECs from apoptosis induced by advanced glycation end products (AGEs). The thoracic aorta was removed from 2-3-year-old Sprague-Dawley rats, and ECs were isolated and cultured. After culturing ECs in the presence of AGEs and/or with HRM for 24 h, Annexin V/7-AAD and TUNEL staining were carried out to detect apoptosis. Intracellular ROS were detected by fluorescent probe and quantified by flow cytometry. The expression of antioxidative enzymes (superoxide dismutase, glutathione peroxidase) was determined by real-time PCR analysis and enzymatic assay. The relative expression levels of Bcl-2 and Bax were analyzed by western blotting. The addition of AGEs increased the apoptosis of ECs in a concentration-dependent manner and HRM reduced the AGE (400 µg/ml)-induced apoptosis from 21.61±2.52 to 11.32±1.75%. HRM also significantly attenuated the AGE-induced intracellular ROS induction and decrease in the expression of antioxidative enzymes. In conclusion, hydrogen exhibits significant protective effects against AGE-induced EC injury possibly through reducing ROS generation, intracellular antioxidant enzyme system protection and elevation of the Bcl-2/Bax ratio.

Overexpression of SDF-1α enhanced migration and engraftment of cardiac stem cells and reduced infarcted size via CXCR4/PI3K pathway.

Cardiac stem cells (CSCs) can home to the infarcted area and regenerate myocardium. Stromal cell-derived factor-1α/C-X-C chemokine receptor type 4 (SDF-1α/CXCR4) axis is pivotal in inducing CSCs migration. However, the mechanisms remain unclear. This study set out to detect if SDF-1α promotes migration and engraftment of CSCs through the CXCR4/PI3K (phosphatidylinositol 3-kinase) pathway. In the in vitro experiment, c-kit+ cells were isolated from neonatal mouse heart fragment culture by magnetic cell sorting. Fluorescence-activated cell sorting results demonstrated that a few c-kit+ cells expressed CD45 (4.54%) and Sca-1 (2.58%), the hematopoietic stem cell marker. Conditioned culture could induce c-kit+ cells multipotent differentiation, which was confirmed by cardiac troponin I (cTn-I), α-smooth muscle actin (α-SMA), and von Willebrand factor (vWF) staining. In vitro chemotaxis assays were performed using Transwell cell chambers to detect CSCs migration. The results showed that the cardiomyocytes infected with rAAV1-SDF-1α-eGFP significantly increased SDF-1α concentration, 5-fold more in supernatant than that in the control group, and subsequently attracted more CSCs migration. This effect was diminished by administration of AMD3100 (10 µg/ml, CXCR4 antagonist) or LY294002 (20 µmol/L, PI3K inhibitor). In myocardial infarction mice, overexpression of SDF-1α in the infarcted area by rAAV1-SDF-1α-eGFP infection resulted in more CSCs retention to the infarcted myocardium, a higher percentage of proliferation, and reduced infarcted area which was attenuated by AMD3100 or ly294002 pretreatment. These results indicated that overexpression of SDF-1α enhanced CSCs migration in vitro and engraftment of transplanted CSCs and reduced infarcted size via CXCR4/PI3K pathway.