Atorvastatin regulates vascular smooth muscle cell phenotypic transformation by epigenetically modulating contractile proteins and mediating Akt/FOXO4 axis.

Atherosclerosis (AS) is a prevalent cardiovascular disease with severe morbidity and high mortality. Phenotypic regulation of vascular smooth muscle cells (VSMCs) from the contractile and quiescent phenotype to the synthetic type is a critical step for the vascular remodeling of AS. Atorvastatin, as a 3­hydroxy­3­methyl­glutaryl coenzyme A reductase inhibitor, presents an anti­inflammatory effect to improve vascular endothelial functions. The aim of the present study was to examine the effect of atorvastatin on VSMCs phenotypic transformation and the underlying mechanism. The rat primary VSMCs were isolated and identified. The protein expression of contractile proteins, such as α­SMA, SM­MHC, and SM22α, was reduced by angiotensin II (AngII) and enhanced by atorvastatin, in which atorvastatin could reverse the effect of AngII in the VSMCs. The treatment of HDAC inhibitor trichostatin A was able to enhance AngII­inhibited expression of α­SMA and SM­MHC. Atorvastatin regulated AngII­associated VSMCs phenotypic transformation by epigenetically regulating contractile proteins. Moreover, atorvastatin modulated platelet­derived growth factor­BB (PDGF­BB)­induced VSMC phenotypic transformation by modulating the Akt/forkhead Box O4 (FOXO4) axis. Immunofluorescence analysis revealed that PDGF­BB enhanced the accumulation of FOXO4 in the VSMCs, while the treatment of atorvastatin was able to attenuate this effect and the co­treatment of Akt inhibitor LY294002 could further inhibit the phenotype. The treatment of PDGF­BB enhanced the interaction of SRF with FOXO4 and myocardin in the VSMCs, in which the co­treatment of atorvastatin and LY294002 could reverse the effect of PDGF­BB in the system. Thus, atorvastatin regulates VSMCs phenotypic transformation by epigenetically modulating contractile proteins and mediating the Akt/FOXO4 axis. Findings of the present study provide new insights into the mechanism by which atorvastatin modulates VSMCs, providing valuable evidence for the application of atorvastatin in the treatment of AS.

Empagliflozin alleviates myocardial I/R injury and cardiomyocyte apoptosis via inhibiting ER stress-induced autophagy and the PERK/ATF4/Beclin1 pathway.

To explore the mechanisms underlying the specific inhibitor targeting SGLT-2 empagliflozin in alleviating myocardial ischaemia-reperfusion (I/R) injury. A mouse model of I/R injury and H2O2-induced H9C2 cell model were established. The expressions of Bcl-2, Bax, LC3, Beclin1, GRP78, CHOP, PERK, ATF4, ATF6, IREα and P62 were examined by western blot, immunofluorescence or immunohistochemistry staining, respectively. The cardiac function was measured by echocardiography, TCC staining, lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) activity. Cell apoptosis was analysed by TUNEL, Annexin V/propidium iodide (PI) staining and caspase 3 and 9 activities. CCK-8 assay was used for analysing cell viability. PBA, TUDC and 3-MA were utilised for blocking ER stress and autophagy, respectively. Empagliflozin suppressed myocardial I/R injury in vivo and H2O2-induced cardiomyocyte apoptosis in vitro. Blockade of ER stress and autophagy inhibited H2O2-induced cardiomyocyte apoptosis. ER stress activated autophagy through the PERK signalling in H2O2-treated H9C2 cells. Empagliflozin suppressed ER stress-induced autophagy by inhibiting the PERK/ATF4/Beclin1 signalling. H2O2 and I/R-induced cardiomyocyte apoptosis was restrained by empagliflozin through inhibition of ER stress-induced autophagy. Empagliflozin suppressed ER stress-induced autophagy via suppressing the PERK/ATF4/Beclin1 signalling, thus alleviating myocardial I/R injury and cardiomyocyte apoptosis.

Saikosaponin-d improved the stemness of mouse neural stem cells and increased their thermotolerance potential.

PURPOSE: To investigate the effect of saikosaponin-d (Ssd) on proliferation, differentiation, and stemness of neural stem cells (NSCs), and to observe whether Ssd has a protective effect on NSCs at medium-high and high temperature. MATERIALS AND METHODS: NSCs were extracted from 15-day fetal mice. After subculture, Ssd treatment was performed. Cell cycle and apoptosis rate were detected by flow cytometry. Western Blot and immunofluorescence assay were used to detect the expression and spatial distribution of Nestin, NSE, GFAP, Oct4, and SOX2. Cell growth morphology was observed under a microscope; the concentration of extracellular lactate dehydrogenase (LDH) was determined by ELISA. RESULTS: Compared with the control group, the proportion of NSCs in the G0/G1 phase increased in the Ssd treatment group; on the contrary, the proportion in the G2/M phase significantly decreased. Microscopically, our results also suggested the sphere-formation rate increased significantly. Besides, the percentage of dead cells in the Ssd group at 38.5, 40°C were reduced, and the level of LDH release was dropped. CONCLUSION: Ssd improved the stemness of NSCs, inhibited their differentiation into neural cells, and reduced cell damage under high temperature. Therefore, we speculate that Ssd can improve the thermotolerance of NSCs and protect the nervous system of children with fever.

[Application evaluation of failure mode and effect analysis in optimization of vascular recanalization process].

OBJECTIVE: To investigate the clinical application and effect evaluation of failure mode and effect analysis (FMEA) in the optimization of vascular recanalization in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 389 STEMI patients admitted to the emergency department of the Fifth Central Hospital in Tianjin from January 2014 to January 2015 were served as the control group, and 398 STEMI patients admitted to the chest pain center of the Fifth Central Hospital in Tianjin from January 2016 to October 2017 were served as the experimental group. In the control group, routine emergency treatment was used. At the same time, the intervention room was 24-hour prepared for emergency vascular recanalization. The experimental group used FMEA. Through the usage of FMEA, the main factors those caused the delay in revascularization treatment were determined, and the revascularization process was optimized for these influencing factors, thereby shortening the "criminal" blood vessel opening time of patients. The door-to-balloon dilatation time (D-to-B time), troponin testing time, placement time of the catheterization room, initiation of the catheterization room to balloon dilatation time, and preoperative and 1 week postoperative N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, heart function parameters [left ventricular ejection fraction (LVEF), left ventricular short axis shortening rate (FS), left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD)] within 1 week, 3 months and 6 months after intervention, and the incidence of main cardiovascular adverse events within 1 month after intervention, hospital mortality, the length of hospital stay, and readmission within 1 year in the patients of two groups were recorded. RESULTS: D-to-B time (minutes: 70.6±3.6 vs. 79.4±8.7), troponin testing time (minutes: 17.1±2.3 vs. 65.2±6.5), placement time of the catheterization room (minutes: 28.9±9.8 vs. 52.3±12.2) and activation of the catheterization room to balloon expansion time (minutes: 47.3±9.3 vs. 65.1±7.2) in the experimental group were significantly shorter than those in the control group (all P < 0.01). The NT-proBNP levels at 1 week after intervention in the two groups were lower than the preoperative levels, slightly lower in the experimental group, but the difference was not statistically significant. There was no significant difference in cardiac function at 1 week and 3 months after intervention between the two groups. The LVEF and FS at 6 months after intervention in the experimental group were significantly higher than those in the control group [LVEF: 0.622±0.054 vs. 0.584±0.076, FS: (38.1±4.3)% vs. (35.4±6.2)%, both P < 0.01], and LVESD and LVEDD were decreased significantly [LVESD (mm): 31.2±3.8 vs. 34.7±4.2, LVEDD (mm): 49.2±5.3 vs. 52.4±5.6, all P < 0.01]. The length of hospital stay in the experimental group was significantly shorter than that in the control group (days: 8.3±3.2 vs. 13.2±6.8, P < 0.01), the incidence of major cardiovascular adverse events within 1 month after intervention [13.6% (54/398) vs. 19.8% (77/389)], hospital mortality [1.8% (7/398) vs. 4.9% (19/389)], and readmission rate within 1 year [9.5% (38/398) vs. 14.5% (56/389)] in the experimental group were significantly lower than those in the control group (all P < 0.05). CONCLUSIONS: The usage of FMEA to optimize the vascular recanalization procedure can shorten the emergency treatment time of STEMI patients, reduce the occurrence of adverse events, and improve the prognosis.

Drug-eluting balloons in the treatment of de-novo coronary lesions: a meta-analysis of randomized-controlled trials.

AIM: The aim of this meta-analysis was to evaluate the efficacy of drug-eluting balloons (DEBs) plus bare-metal stents (BMS) for the treatment of de-novo coronary lesions. METHODS AND RESULTS: Eleven trials involving 1279 patients were included in this study. The main endpoints were as follows: late lumen loss (LLL), binary restenosis, stent thrombosis (ST), and major adverse cardiovascular events (MACEs). The definition of MACEs was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR). Compared with BMS alone, DEB plus BMS showed a lower risk for LLL (P=0.007) and MACEs (P=0.010). There were no significant differences in binary restenosis (P=0.212), ST (P=0.199), death (P=0.141), MI (P=0.439), and TLR (P=0.340). Compared with drug-eluting stents (DES), DEB plus BMS could increase the risk of LLL (P=0.002) and MACEs (P=0.026). The risks of binary restenosis (P=0.113), ST (P=0.832), death (P=0.115), MI (P=0.831), and TLR (P=0.111) were similar between DEB plus BMS and DES. CONCLUSION: DEB plus BMS was better than BMS alone in reducing LLL and MACEs, especially when dilatation was performed after stenting for de-novo coronary lesions, but it was inferior to DES. Therefore, the treatment strategy with DEB plus BMS should not be recommended for de-novo coronary lesions, except for patients who have contraindications for DES.

The role of leptin in the ventricular remodeling process and its mechanism.

OBJECTIVE: This study aims to explore the role of leptin in the ventricular remodeling process and its mechanism in the diabetic rats' model. METHODS: The diabetic SD rats model induced by streptozotocin was established. The SD rats were randomly divided into 4 groups: control group (20 rats treated with citric acid/sodium citrate buffer); M0 group (10 rats treated with physiological saline); M1 group (10 rats treated with 50 µg/kg LP); M2 group (10 rats treated with 100 µg/kg LP). Ang-II was detected by ELISA. The expression levels of LP and Ob-Rb were detected by RT-PCR. MAPK phosphorylation changes were detected by western blotting. Myocardial morphology was observed. RESULTS: Compared with control group, the blood glucose concentration and Ang-II significantly increased in diabetic model groups (P < 0.01) and body weight decreased (P < 0.05). The expression levels of LP and Ob-Rb increased and heart function decreased in diabetic model groups. CONCLUSIONS: LP may be involved in the myocardial cell hypertrophy through the neuroendocrine system and associated with the JAK-STAT, Ras-Raf-MEK-MAPK and PI-3K signaling pathway, which provides a new concept for the pathogenesis of cardiac hypertrophy.

Effects of tirofiban on platelet activation and endothelial function in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention.

This pilot study examined, for the first time, the effect of intracoronary administration of tirofiban, an inhibitor of platelet aggregation, on platelet activation and endothelial dysfunction in patients with ST-segment-elevated myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). A total of 119 STEMI patients were randomized into either tirofiban group (n = 72, intracoronary injection of 10 µg/kg tirofiban prior to PCI, followed by intravenous infusion at 0.15 µg/kg min) or a control group (n = 47), which did not receive tirofiban. Periprocedural administration of tirofiban was associated with significantly reduced levels of platelet activation (lower levels of CD62P and PAC-1) and endothelial dysfunction (reduced levels of endothelial microparticles, VCAM-1, and ICAM-1) 48 h after PCI. At 10 days after PCI, patients in the tirofiban group had a higher incidence of complete STR (78.7 vs. 65.0%) and higher left ventricular ejection fractions (47.8 vs. 44.2) compared to those in the control group. The clinical outcomes between two groups did not differ significantly two weeks after treatment. The results demonstrated that periprocedural administration of tirofiban is associated with significantly attenuated platelet activation and endothelial dysfunction in STEMI patients undergoing PCI. This may have contributed to the improved myocardial reperfusion and preservation of left ventricular systolic function in these patients.

Correlation between brachial-ankle pulse wave velocity, carotid artery intima-media thickness, ankle-brachial index, and the severity of coronary lesions.

Coronary angiography is the gold standard for the diagnosis of coronary artery disease. Coronary artery Gensini scoring systems measure both the extent and the degree of stenosis of coronary artery and therefore, give clinicians a more accurate, objective, and comprehensive assessment of the severity of coronary artery disease. Using Gensini scoring systems in combination with statistical analysis, we found that five variables, namely, Brachial-ankle pulse wave velocity (PWV), ankle-brachial index (ABI), carotid artery intima-media thickness (IMT), blood sugar, and high density lipoprotein cholesterol (HDL-C), were all significantly different among groups of patients with different Gensini scores. All five variables can be used for early screening and assessment of coronary artery disease as independent prognostic factors for the morbidity and mortality from cardiovascular conditions. With the progression of coronary artery disease, the levels of PWV, IMT, and blood glucose are gradually increasing whereas the levels of ABI and HDL-C are gradually decreasing. These changes can be treated as warning signs and can also be helpful in evaluating the severity of coronary artery diseases. It is highly recommended to perform these five non-invasive tests as early as possible in order to identify high-risk patients at their subclinical stages. This would allow timely intervention and thereby lead to reduced morbidity and mortality from cardiovascular diseases.