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Background Percutaneous coronary intervention (PCI) of a long calcified coronary lesion in patients with chronic kidney disease (CKD) is challenging and can lead to stent under-expansion and contrast-induced acute kidney injury (CI-AKI). We described the first case of intravascular ultrasound (IVUS)-guided reverse overlapping stenting of long calcified left anterior descending (LAD) coronary lesion using ultra-low contrast and the metallic roadmaps to prevent CI-AKI after PCI. Case summary A 77-year-old man with a history of hypertension, type 2 diabetes, and CKD was admitted with angina class 4 and ruled in for non-ST-elevation myocardial infarction. His ejection fraction was 40%. He was referred for cardiac catheterization and PCI. Coronary angiography showed a long calcified stenosis of the LAD. IVUS catheter was advanced at least 10 mm distal to the lesion or stent edge. IVUS images were obtained with automated pullback (1 mm/s) using a commercially available IVUS system with a 60-MHz mechanical transducer (Boston Scientific, Natick, Massachusetts). IVUS showed calcified plaque fractures after balloon angioplasty and intracoronary lithotripsy. The first stent was deployed proximally using the guidewire in the diagonal branch as a metallic roadmap, and the second stent was deployed distally overlapping at the distal edge of the first stent as a roadmap with no contrast injection. Percutaneous coronary intervention was completed successfully using only 12 mL contrast. Glomerular filtration rate remained stable after PCI. Glomerular filtration rate and ejection fraction improved at 12-month follow-up. Discussion We described the first case of the reverse overlapping stenting technique guided by IVUS with no contrast in a patient with CKD and a long calcified LAD lesion. Conventionally, in long lesions, the first stent is deployed distally and the second stent proximally, which requires contrast injection for stent deployment. We demonstrated that the above technique resulted in preventing CI-AKI and improving creatinine as well as ejection fraction at follow-up. [ABSTRACT FROM AUTHOR]

Coronary stent underexpansion is associated with restenosis and stent thrombosis. In clinical studies of atherosclerosis, high wall shear stress (WSS) has been associated with activation of prothrombotic pathways, upregulation of matrix metalloproteinases, and future myocardial infarction. We hypothesized that stent underexpansion is predictive of high WSS. WSS distribution was investigated in patients enrolled in the prospective randomized controlled study of angulated coronary arteries randomized to undergo percutaneous coronary intervention with R-ZES or X-EES. WSS was calculated from 3D reconstructions of arteries from intravascular ultrasound (IVUS) and angiography using computational fluid dynamics. A logistic regression model investigated the relationship between WSS and underexpansion and the relationship between underexpansion and stent platform. Mean age was 63±11, 78% were male, 35% had diabetes, mean pre-stent angulation was 36.7°±14.7°. Underexpansion was assessed in 83 patients (6,181 IVUS frames). Frames with stent underexpansion were significantly more likely to exhibit high WSS (> 2.5 Pa) compared to those without underexpansion with an OR of 2.197 (95% CI = [1.233–3.913], p = 0.008). There was no significant association between underexpansion and low WSS (< 1.0 Pa) and no significant differences in underexpansion between R-ZES and X-EES. In the Shear Stent randomized controlled study, underexpanded IVUS frames were more than twice as likely to be associated with high WSS than frames without underexpansion. [ABSTRACT FROM AUTHOR]

Purpose: This study was to analyze the incidence of definite stent thrombosis (ST) after the implantation of drug-eluting stents (DESs) and cutoff value of overlapping length for predicting definite ST. An overlapping stent is associated with a high rate of clinical events after DES implantation compared with a non-overlapping stent. However, the rates of definite ST and clinical outcomes from a large patient population remain underreported. Methods: A total of 15,561 patients with 24,183 lesions who underwent DES implantation from January 2005 to February 2017 were retrospectively included in 5 tertiary hospitals in China. The main endpoint was the incidence of definite ST after procedures. Results: With a median of 1932 (IQR = 1194–2929) days, clinical follow-up was available in 7484 patients in the overlap group and in 8077 patients in the non-overlap group. The rates of definite ST were 3.1% in the overlap group and 1.2% in the non-overlap group (HR: 2.67 (95% CI: 2.11–3.38), p < 0.001). Of the 24,183 treated lesions, the incidences of definite ST were 2.4% in the overlap group and 0.9% in the non-overlap group (HR: 2.96 (95% CI: 2.38–3.69), p < 0.001). Stent overlap was associated with a higher rate of target lesion revascularization (TLR) (9.4%) compared with stent non-overlap (6.4%, p < 0.001). The length of overlapping stent ≥ 2.93 mm strongly correlated with definite ST. Conclusion: The present study shows that overlapping DES increases definite ST and revascularization in patients during long-term follow-up. In addition, the longer overlapping zone was associated with worse clinical outcomes. [ABSTRACT FROM AUTHOR]

In artery tree, endothelial function correlates with the distribution of shear stress, a dragging force generated by flowing blood. In laminar shear stress areas, endothelial cells (ECs) are available to prevent atherosclerosis, however, ECs in disturbed shear stress sites are featured with proinflammation and atherogenesis. Basic studies in the shear stress field that focused on the mechanosensors of ECs have attracted the interest of researchers. Among all the known mechanosensors, the primary cilium is distinctive because it is enriched in disturbed shear stress regions and sparse in laminar shear stress areas. The primary cilium, a rod liked micro-organelle, can transmit extracellular mechanical and chemical stimuli into intracellular space. In the cardiovascular system, primary cilia are enriched in disturbed shear stress regions, where blood flow is slow and oscillatory, such as the atrium, downstream of the aortic valve, branches, bifurcations, and inner curves of the artery. However, in the atrioventricular canal and straight vessels, blood flow is laminar, and primary cilia can barely be detected. Primary cilia in the heart cavity prevent ECs from mesenchymal transition and calcification by suppressing transforming growth factor (TGF) signaling. Besides, primary cilia in the vascular endothelium protected ECs against disturbed shear stress-induced cellular damage by triggering Ca2+ influx as well as nitric oxide (NO) release. Moreover, primary cilia inhibit the process of atherosclerosis. In the current review, we discussed ciliogenesis, ciliary structure, as well as ciliary distribution, function and the coordinate signal transduction with shear stress in the cardiovascular system. [ABSTRACT FROM AUTHOR]

Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel‐mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150−/−) and wild‐type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150−/− diabetic mice. Impaired Akt/GSK3β signalling contributed to decreased BK‐β1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK‐β1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK‐β1 expression, and treatment with AKAP150 siRNA suppressed GSK3β expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel‐mediated vascular dysfunction through the Akt/GSK3β signalling pathway in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is the end‐stage syndrome for most cardiac diseases, and the 5‐year morbidity and mortality of HF remain high. Malignant arrhythmia is the main cause of sudden death in the progression of HF. Recently, bridging integrator 1 (BIN1) was discovered as a regulator of transverse tubule function and calcium signalling in cardiomyocytes. BIN1 downregulation is linked to abnormal cardiac contraction, and it increases the possibility of malignant arrhythmias preceding HF. Because of the detectability of cardiac BIN1 in peripheral blood, BIN1 may serve as a predictor of HF and may be useful in therapy development. However, the mechanism of BIN1 downregulation in HF and how BIN1 regulates normal cardiac function under physiological conditions remain unclear. In this review, recent progress in the biological studies of BIN1‐related cardiomyocytes and the effect of cardiac dysfunction and malignant arrhythmia will be discussed. [ABSTRACT FROM AUTHOR]

Purpose of Review: Sympathetic overactivity plays an important role in the progression of pulmonary arterial hypertension (PAH). The purpose of this review is to illustrate localization of pulmonary arterial sympathetic nerves, the key steps of pulmonary artery denervation (PADN) procedure, and to highlight clinical outcomes. Recent Findings: Sympathetic nerves mostly occurred in the posterior region of the bifurcation and pulmonary trunk. Emerging preclinical data provided the potential of PADN for PAH. PADN, produced at bifurcation area, improved a profound reduction of pulmonary arterial pressure and ameliorated clinical outcomes with an exclusive ablation catheter. The application of PADN in the patients of PAH or combined pre-capillary and post-capillary PH (CpcPH) improved the hemodynamic parameters and increased 6MWD. Summary: Sympathetic overactivity aggravates PAH. PADN is a promising interventional treatment for PAH and CpcPH. Additional clinical trials are warranted to confirm the efficacy of PADN. [ABSTRACT FROM AUTHOR]

Intravascular ultrasound (IVUS) guidance is not routinely performed in real-word clinical practice partly because the benefit of IVUS guidance is not well established. This updated meta-analysis aims to compare IVUS-guided and angiography-guided drug-eluting stent (DES) implantation, simultaneously stressing the value of an optimal IVUS-defined procedure. Medline, Scopus, Google Scholar, and Cochrane Controlled Trials Registry were searched for the randomized trials comparing IVUS-guided and angiography-guided DES implantation. Nine eligible randomized trials including 4,724 patients were identified. At a mean follow-up of 16.7 months, IVUS guidance was associated with a significant lower risk of major adverse cardiovascular events (MACE) [5.4% vs. 9.0%; relative risks (RR): 0.61, 95% confident interval (CI) 0.49-0.74, p < 0.001], cardiac death (0.6% vs. 1.2%; RR: 0.49, 95% CI 0.26-0.92, p = 0.03), target vessel revascularization (3.5% vs .6.1%; RR: 0.58, 95% CI 0.42-0.80, p = 0.001), target lesion revascularization (3.1% vs. 5.2%; RR: 0.59, 95% CI 0.44-0.80, p = 0.001), and definite/probable stent thrombosis (0.5% vs .1.1%; RR: 0.45, 95% CI 0.23-0.87, p = 0.02) compared with angiography guidance. No significant differences in all cause death and myocardial infarction were noted between the two groups. Subgroup analysis showed that patients who met the optimal criteria had a lower rate of MACE than those with IVUS-defined suboptimal procedure (RR: 0.33, 95% CI 0.06-0.60, p = 0.02). The present meta-analysis with the largest sample size to date demonstrates that IVUS-guided DES implantation significantly reduces cardiac death, coronary revascularization and stent thrombosis, particularly for patients with IVUS-defined optimal procedures compared with angiography guidance. [ABSTRACT FROM AUTHOR]

Background: Norepinephrine (NE)‐mediated vasoconstriction plays an important role in pulmonary hypertension associated with left heart disease (PH‐LHD). However, the role of NE‐mediated endothelial cell dysfunction in the pathogenesis of PH‐LHD remains to be elucidated. Methods and Results: An enzyme‐linked immunosorbent assay showed that the NE concentration in the plasma of patients with PH‐LHD was higher and the nitrate–nitrite concentration was lower than those in the control group. NE treatment decreased phospho‐Ser633‐eNOS and β2‐adrenergic receptor (β2‐AR) levels in the membrane of human pulmonary artery endothelial cells (HPAECs) analysed by western blot analysis. Consistently, fluorescence microscopy and flow cytometry showed that nitric oxide (NO) production was also decreased in HPAECs. Coimmunoprecipitation confirmed a direct interaction between β2‐AR and endothelial NO synthase (eNOS). Overexpression of β2‐AR attenuated the decline in phospho‐Ser633‐eNOS and NO production. Additionally, the expression of phospho‐Ser633‐eNOS and β2‐AR was decreased in human pulmonary artery endothelium. Finally, our results indicate that NE stimulated HPAEC proliferation, which was blocked by protein kinase A inhibitor or protein kinase B (PKB–AKT) inhibitor. Conclusions: These data provide a novel mechanism for NE‐decreased endothelium‐derived NO and NE‐induced HPAEC proliferation that leads to PH‐LHD, suggesting a potential therapeutic target for PH‐LHD. These data provide a novel mechanism for norepinephrine (NE)‐decreased endothelium‐derived nitric oxide and NE‐induced human pulmonary artery endothelial cells proliferation that leads to pulmonary hypertension associated with left heart disease (PH‐LHD), suggesting a potential therapeutic target for PH‐LHD. [ABSTRACT FROM AUTHOR]

Climatic stresses limit plant growth and productivity. In the past decade, tree improvement programs were mainly focused on yield but it is obvious that enhanced stress resistance is also required. In this review we highlight important drought avoidance and tolerance mechanisms in forest trees. Genomes of economically important trees species with divergent resistance mechanisms can now be exploited to uncover the mechanistic basis of long-term drought adaptation at the whole plant level. Molecular tree physiology indicates that osmotic adjustment, antioxidative defense and increased water use efficiency are important targets for enhanced drought tolerance at the cellular and tissue level. Recent biotechnological approaches focused on overexpression of genes involved in stress sensing and signaling, such as the abscisic acid core pathway, and down-stream transcription factors. By this strategy, a suite of defense systems was recruited, generally enhancing drought and salt stress tolerance under laboratory conditions. However, field studies are still scarce. Under field conditions trees are exposed to combinations of stresses that vary in duration and magnitude. Variable stresses may overrule the positive effect achieved by engineering an individual defense pathway. To assess the usability of distinct modifications, large-scale experimental field studies in different environments are necessary. To optimize the balance between growth and defense, the use of stress-inducible promoters may be useful. Future improvement programs for drought resistance will benefit from a better understanding of the intricate networks that ameliorate molecular and ecological traits of forest trees. [ABSTRACT FROM AUTHOR]

ATP‐sensitive potassium channels (KATP) channels are widely distributed in various tissues, including pancreatic beta cells, muscle tissue and brain tissue. KATP channels play an important role in cardioprotection in physiological/pathological situations. KATP channels are inhibited by an increase in the intracellular ATP concentration and are stimulated by an increase in the intracellular MgADP concentration. Activation of KATP channels decreases ischaemia/reperfusion injury, protects cardiomyocytes from heart failure, and reduces the occurrence of arrhythmias. KATP channels are involved in various signalling pathways, and their participation in protective processes is regulated by endogenous signalling molecules, such as nitric oxide and hydrogen sulphide. KATP channels may act as a new drug target to fight against cardiovascular disease in the development of related drugs in the future. This review highlights the potential mechanisms correlated with the protective role of KATP channels and their therapeutic value in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested that exogenous hydrogen sulfide can alleviate the development of diabetic cardiomyopathy (DCM) by inhibiting oxidative stress, inflammation, and apoptosis. However, the underlying mechanism is not fully understood. Nuclear expression and function of the transcription factor Forkhead box protein O (FoxO1) have been associated with cardiovascular diseases, and thus, the importance of FoxO1 in DCM has gained increasing attention. This study was designed to investigate the interactions between hydrogen sulfide (H2S) and nuclear FoxO1 in DCM. Methods: Diabetes was induced in adult male C57BL/6J mice by intraperitoneal injection of streptozotocin and was treated with H2S donor sodium hydrosulfide for 12 weeks. The H9C2 cardiomyoblast cell line and neonatal rat cardiomyocytes (NRCMs) were treated with the slow‐releasing H2S donor GYY4137 before high‐glucose (HG) exposure with or without pretreatment with the Akt inhibitor MK‐2206 2HCl. Changes in FoxO1 protein phosphorylation and subcellular localization were determined in H9C2 cells, NRCMs, and cardiac tissues from normal and diabetic mice. Cardiac structure and function in the diabetic mice were evaluated by echocardiography and histological analysis and compared with those in control animals. Results: The echocardiographic and histopathological data indicated that exogenous H2S improved cardiac function and attenuated cardiac hypertrophy and myocardial fibrosis in diabetic mice. H2S also improved HG‐induced oxidative stress and apoptosis in cardiac tissue and NRCMs. In addition, H2S induced FoxO1 phosphorylation and nuclear exclusion in vitro and in vivo, and this function was not inhibited by MK‐2206 2HCl. Alanine substitution mutation of three sites in FoxO1‐enhanced FoxO1 transcriptional activity, and subsequent treatment with exogenous H2S could not prevent HG‐induced nuclear retention. Conclusions: Our data indicate that H2S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H2S in inhibiting the progression of DCM. Our data indicate that hydrogen sulfide (H2S) is a novel regulator of Forkhead box protein O in cardiac cells and provide evidence supporting the potential of H2S in inhibiting the progression of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Stenting coronary artery bifurcation lesion is associated with suboptimal clinical results. Clinical improvement by intravascular ultrasound (IVUS) guided bifurcation stenting is controversial because small-side-branch (SB), low-risk patients and false bifurcations were included in previous studies that had no exact IVUS criteria for optimal stent expansion. We sought determine whether IVUS guidance is superior to angiography guidance for patients with true and complex bifurcation lesions. Between July 2006 and July 2012, 1465 patients with unstable angina and Medina 1,1,1 or 0,1,1 coronary bifurcation lesions were prospectively studied. 310 patients in the IVUS guidance (defined as stent symmetry index > 0.7, stent expansion index > 0.9, well apposition, and no Type B/C dissection) group were paired with 620 patients in the angiography group by propensity score-matching. The primary endpoint was the rate of composite major adverse cardiac events (MACE) (cardiac death, myocardial infarction (MI), or clinically-driven target vessel revascularization) at 1-year and at the end of study after indexed procedure. Use of IVUS guidance was mainly driven by stenting technique selection and identification of lesions' specificities. IVUS criteria for optimal stent expansion were achieved in 82.9% of patients which contribute to IVUS group data assessment and the rest did not meet optimal criteria. MACE occurred in 10.0% of patients at 1-year follow-up and 15.2% at the 7-year follow-up in the IVUS group, significantly different from 15.0% (p = 0.036) and 22.4% (p = 0.01) in the angiography group, respectively. Compared to angiography guidance, IVUS guidance also resulted in a lower 7-year cardiac death rate (6.5 versus 1.3%, p = 0.002) and MI (8.4 versus 2.3%, P < 0.001). Any revascularization was also statistically lower in the IVUS group through whole study period, compared to the angiography group. Lower MACE rates were observed in IVUS guidance group in a 7-year follow-up compared with angiography guidance alone. [ABSTRACT FROM AUTHOR]

Background: The relationship between platelet reactivity and long-term clinical outcomes remains controversial. The present prospective study was designed to explore the association between high platelet reactivity (HPR) on clopidogrel and long-term clinical outcomes following implantation of drug eluting stents (DES).Methods: A total of 1769 consecutive patients assessed by Aggrestar (PL-11) were enrolled at our center from February 2011 to December 2017. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCE), defined as definite or probable stent thrombosis, spontaneous myocardial infarction, all cause death, clinically driven target vessel revascularization (TVR), or ischemic stroke. Bleeding served as the safety endpoint. Propensity score matching (PSM) analysis was performed to adjust for baseline differences in the overall cohort.Results: Finally, 409 patients (23.1%) were identified with HPR on clopidogrel. At a median follow-up of 4.1 years (interquartile range, 1.8 years), the occurrence of MACCE was significantly higher in HPR on clopidogrel group than normal platelet reactivity (NPR) on clopidogrel group (15.6% vs. 5.4%, p < 0.001). After PSM, 395 paired patients were matched, and the difference in MACCE between HPR (15.7%) versus NPR (9.4%) on clopidogrel groups remained significant (P < 0.001), mainly driven by increased all cause death (5.3% vs. 1.8%, p < 0.001), and clinically driven TVR (8.1% vs. 6.3%, p = 0.019) in the HPR group. The risk of bleeding between two groups was similar.Conclusions: This prospective study confirms the relationship between HPR on clopidogrel and long-term adverse cardiovascular events after coronary stenting. [ABSTRACT FROM AUTHOR]

MicroRNA‑210 (miRNA‑210) has been reported to be associated with angiogenesis and may serve important roles in acute myocardial infarction (AMI), which remain unclear. The present study sought to evaluate the efficacy of miRNA‑210 in AMI and to examine the potential associated mechanisms. AMI models were established in Sprague‑Dawley rats. The expression of miRNA‑210 was upregulated via transfection with lentivirus‑mediated agonists and quantitative analysis was performed using the reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Immunoblotting and RT‑qPCR were separately used to detect the expression levels of hepatocyte growth factor (HGF) in heart samples, while only the protein expression level of β‑myosin heavy chain (β‑MHC) was assessed. The expression of HGF in human umbilical vein endothelial cells under hypoxic conditions was silenced by transfecting with small interfering RNA, as demonstrated by the determination of associated protein expression levels. The microvessel density (MVD) of the infarcted myocardium was selected to be the angiogenesis efficacy endpoint, which was evaluated by platelet endothelial cell adhesion molecule immunostaining. Markedly increased expression of HGF was observed among the AMI rats receiving miRNA‑210 agonists, demonstrated via quantitative analyses using RT‑qPCR or western blotting. Promotion of angiogenesis was observed with the increased MVD. Improved cardiac function in the rats was subsequently noted, as they exhibited improved left ventricular fractional shortening and left ventricular ejection fraction percentages, which may result from improved cardiac contractility indicated by attenuating the increase in β‑MHC protein expression. Overexpression of miRNA‑210 appeared to be an advantageous therapeutic tool for treating AMI, primarily due to its promoting effects on angiogenesis in the infarcted myocardium by stimulating HGF expression and inducing improved left ventricular remodeling, leading to improved cardiac function. [ABSTRACT FROM AUTHOR]

Type 2 diabetes correlates with clinical events after the implantation of a second-generation drug-eluting stent (DES). The rate and prognostic value of stent fracture (SF) in patients with diabetes who underwent DES implantation remain unknown. A total of 1160 patients with- and 2251 without- diabetes, who underwent surveillance angiography at 1 year after DES implantation between June 2004 and August 2014, were prospectively studied. The primary endpoints included the incidence of SF and a composite major adverse cardiac event [MACE, including myocardial infarction (MI), cardiac death, and target-vessel revascularization (TVR)] at 1-year follow-up and at the end of follow-up for overall patients, and target lesion failure [TLF, including cardiac death, target vessel myocardial infarction (TVMI) and target lesion revascularization (TLR)] at the end of study for SF patients. In general, diabetes was associated with a higher rate of MACE at 1-year (18.4 vs. 12.9%) and end of follow-up (24.0 vs. 18.6%, all p < 0.001), compared with those in patients who did not have diabetes. The 1-year SF rate was comparable among patients with diabetes (n = 153, 13.2%) and non-diabetic patients (n = 273, 12.1%, p > 0.05). Diabetic patients with SF had a 2.6-fold increase of SF-related cardiac death at the end of study and threefold increase of re-repeat TLR when compared with non-diabetic patients with SF (5.9 vs. 2.2%, p = 0.040; 6.5 vs. 2.2%, p = 0.032), respectively. Given the fact that diabetes is correlated with increased MACE rate, SF in diabetic patients translates into differences in mortality and re-repeat TLR compared with the non-diabetic group. [ABSTRACT FROM AUTHOR]

Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3β-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3β was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3β expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3β and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg−1-d−1, significantly suppressed GSK-3β activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3β-PP2A-NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

The study sought to compare long-term optical coherence tomography (OCT)-based in-stent vascular response between the abluminal groove-filled biodegradable polymer sirolimus-eluting stent (SES) and the durable polymer everolimus-eluting stent (EES) in the TARGET I trial. The TARGET I trial was a prospective, multicenter, randomized clinical trial which enrolled 458 patients with single de novo lesions treated by abluminal groove-filled biodegradable polymer SES and EES. A subset of 43 patients underwent angiography and OCT examinations at 3 years. All OCT images were analyzed at 0.4 mm intervals. A similar increase in angiographic late lumen loss was observed in SES and EES (from 0.05 ± 0.05 vs. 0.05 ± 0.05 mm [p = 0.84] at 9 months to 0.25 ± 0.37 vs. 0.26 ± 0.19 mm [p = 0.99] at 3 years, respectively), without significant differences at 3 years in mean neointimal thickness of stent struts (SES: 0.13 ± 0.02 mm vs. EES: 0.13 ± 0.02 mm, p = 0.80); mean percentage of covered struts (SES: 99.2 % vs. EES: 99.3 %, p = 0.53), or malapposed strut rates (SES: 0.08 % vs. EES: 0.06 %, p = 0.15). The OCT-based in-stent vascular response evaluation found similar vascular healing for the two studied devices, indicating that the luminal loss in EES from 9 months to 3 years cannot be imputed on its coated biocompatible polymer. [ABSTRACT FROM AUTHOR]

In higher plants, the salt overly sensitive ( SOS) signalling pathway plays a crucial role in maintaining ion homoeostasis and conferring salt tolerance under salinity condition. Previously, we functionally characterized the conserved SOS pathway in the woody plant Populus trichocarpa. In this study, we demonstrate that overexpression of the constitutively active form of Pt SOS2 ( Pt SOS2 TD), one of the key components of this pathway, significantly increased salt tolerance in aspen hybrid clone Shanxin Yang ( Populus davidiana × Populus bolleana). Compared to the wild-type control, transgenic plants constitutively expressing Pt SOS2 TD exhibited more vigorous growth and produced greater biomass in the presence of high concentrations of NaCl. The improved salt tolerance was associated with a decreased Na+ accumulation in the leaves of transgenic plants. Further analyses revealed that plasma membrane Na+/H+ exchange activity and Na+ efflux in transgenic plants were significantly higher than those in the wild-type plants. Moreover, transgenic plants showed improved capacity in scavenging reactive oxygen species ( ROS) generated by salt stress. Taken together, our results suggest that Pt SOS2 could serve as an ideal target gene to genetically engineer salt-tolerant trees. [ABSTRACT FROM AUTHOR]

Insecticide resistance is an evolutionary adaptation that develops quite quickly in mosquitoes because of the high selection pressure of chemical insecticides, rapid generation time and large population size. Identification of genes associated with insecticide resistance is fundamental to understand the complex processes responsible for resistance. We compared the gene transcriptional profiles of parathion-resistant and -susceptible Culex pipiens quinquefasciatus using a combination of suppression subtractive hybridization and complementary DNA (cDNA) microarray techniques. A total of 278 colonies were selected from the resistant-susceptible mosquito subtractive library, 38 of which showed more than two fold stronger immunoblotting signals in the resistant strain than in the susceptible strain using cDNA microarray selection. The sequencing results showed that the 38 colonies can be matched to 12 genes of C. p. quinquefasciatus. Eight genes were confirmed to be overexpressed by more than two fold in the resistant strain. These genes encode chymotrypsin-1, theta glutathione S-transferase, lipase 3, larval serum protein 1 β chain, cytochrome b, mitochondrial ribosomal large subunit, 28S rRNA, and a protein with unknown function. This study serves as a preliminary attempt to identify new genes associated with organophosphate resistance in this mosquito species and provides insights into the complicated physiological phenomenon of insecticide resistance. [ABSTRACT FROM AUTHOR]

The present study aimed to test the hypothesis that berberine, a plant-derived anti-oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction ( MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague-Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC-3B, Beclin-1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high-dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post- MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC-3B II and Beclin-1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho-Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho-Akt signalling pathways. [ABSTRACT FROM AUTHOR]

Background Evidences concerning the predictive value of baseline inflammatory biomarkers after drug-eluting stent (DES) placement are controversial, mainly because the use of statin was not precisely defined. Objectives The aim was to compare the differences between interleukin (IL)-6 and high-sensitivity C-reactive protein (hs-CRP) in predicting cardiovascular events 2 years after stenting in patients with unstable angina (UA) who had not received statin pretreatment. Methods There were 1,896 patients included in this study. The primary end-point was the occurrence of cardiac death or myocardial infarction (MI). Secondary endpoints included all-cause death, stent thrombosis (ST), target lesion revascularization (TLR), target vessel revascularization (TVR), or a composite of major adverse cardiac events (MACE) at 2 years after the procedure. Results During the median follow-up of 2.77 years, 96 patients experienced cardiac death (n = 37, 1.95%) or MIs (n = 70, 3.69%), 94 TLRs, 123 TVRs, 215 MACEs, and 21 definite or probable STs. In multivariable Cox proportional-hazards models and discrimination analysis, elevated IL-6 levels were superior to hs-CRP in predicting the occurrence not only of cardiac death or MI (HR 1.337, 95% CI 1.234-1.449, P < 0.001), but also of MACE and late-occurring definite/probable ST. Incorporation of IL-6 into conventional variables resulted in significantly increased c statistic for the prediction of end-points, with the exception of TLR and TVR. Conclusion Elevated IL-6 levels were independent predictors of cardiac death or MI, MACE, and late ST in patients with UA who had not received statin pretreatment, suggesting a role for IL-6 in the inflammatory risk assessment. Pathological studies have confirmed that atherosclerosis is a chronic inflammatory disease. Serum levels of high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase, plasminogen activator inhibitor-1, the complement components C3a or C5a, and interleukin(IL)-6 were reported to provide strong and independent indications of the risk for future cardiovascular (CV) events, even among individuals who are thought to be free of vascular disease. (J Interven Cardiol 2014;27:142-154) [ABSTRACT FROM AUTHOR]

Background: Some clinical studies have demonstrated that the proton pump inhibitor (PPI) could decrease clopidogrel platelet response and increase major adverse cardiovascular events (MACE) in white or black subjects. However, that remains to be determined in Chinese patients. In this study, we sought to determine whether there could be an increased risk for developing MACE after concomitant use of dual antiplatelet therapy (DAT) and a PPI in Chinese patients treated with percutaneous coronary intervention (PCI) and stenting. Methods: This study was a 5-year, single-center, retrospective cohort analysis of eligible patients (n = 6188) who received DAT and a PPI concomitantly (defined as PPI users) before discharge and/or 12-month follow-up after discharge as compared with those who received DAT alone (also defined as non-PPI users, n = 1465). The incidence of recurrent MACE, such as myocardial infarction (MI), definite stent thromboses (ST), or cardiovascular death, was compared between the PPI users and non-users. Results: PPI users had a significantly higher incidence of the MACE than non-users (13.9% vs. 10.6%; adjusted HR: 1.33; 95% CI: 1.12 – 1.57, P = 0.007). Stratified analysis revealed that concurrent use of DAT and a PPI was associated with a significantly increased risk for developing ST compared with DAT alone (1% vs. 0.4%; adjusted HR: 2.66, 95% CI: 1.16 – 5.87, P = 0.012). However, there were no significant differences in the risk of MI, cardiovascular death and other adverse events, regardless of combination of clopidogrel and a PPI. Conclusions: The study further suggests that concomitant use of DAT and a PPI may be associated with an increased risk for developing MACE, in particular definite ST, in Chinese PCI patients after discharge as compared with use of DAT alone. [ABSTRACT FROM AUTHOR]

Multidrug resistance protein 3 ( MPR3), encoded by the ATP-binding cassette, subfamily C ( CFTR/ MRP), member 3 ( ABCC3) gene, functions as an important drug efflux transporter. The ABCC3 -211 C/ T polymorphism is associated with decreased MRP3 mRNA expression, and low MRP3 mRNA expression is associated with increased clopidogrel response in patients. The aim of the present study was to determine whether the -211 C/ T polymorphism is associated with altered antiplatelet effects and clinical outcomes in clopidogrel-treated patients., A subcohort of 249 patients not carrying the CYP2C19* 2, * 3 or * 17 variant was identified from a total of 617 consecutive clopidogrel-treated patients undergoing percutaneous coronary intervention and then categorized into three groups on the basis of their ABCC3 -211 C/ T genotype. Baseline data, clinical characteristics and DNA samples were collected for all patients. Light transmittance aggregometry was used to determine ADP-induced maximum platelet aggregation ( MPA) in blood samples obtained from patients on Day 3 after starting daily clopidogrel maintenance doses. Genotyping of CYP2C19* 2, * 3 and * 17 variants and the ABCC3 -211 C/ T polymorphism was performed using matrix-assisted laser desorption ionization time-of-flight ( MALDI- TOF) mass spectrometry. The primary clinical end-point was a definite stent thrombosis ( ST) episode, whereas secondary end-points were other major adverse cardiovascular events within 12 months after stenting., There were no differences in MPA values according to ABCC3 -211 C/ T genotype. A multiple linear regression model revealed that the ABCC3 -211 C/ T polymorphism was not independently associated with ADP-induced MPA measurements; a multiple logistic regression model revealed that carrying the ABCC3 -211 C allele was not associated with the risk of developing an ST event in clopidogrel-treated patients not harbouring CYP2C19* 2, * 3 and * 17 variants., In conclusion, the ABCC3 -211 C/ T polymorphism seems not to be associated with altered antiplatelet effects and clinical outcomes in clopidogrel-treated patients. [ABSTRACT FROM AUTHOR]

Background Polymer-free sirolimus- and probucol-eluting stents ( Real Dual drug-eluting stents [ DES]) is as effective as first-generation DES in treating coronary artery stenosis. It is unknown whether sirolimus-eluting stents containing biodegradable polymer ( Excel) would be superior to real Dual DES. This study aimed to investigate the difference in target vessel revascularization ( TVR) at 12 months in patients with coronary artery disease treated by the implantation of Dual DES or Excel stents. Methods Three hundred and forty-six patients with de novo coronary artery disease were recruited from six centers in China and randomly assigned to either the Dual DES or the Excel group. The primary endpoint was the occurrence of TVR at 12 months. The secondary endpoint was angiographic in-stent restenosis and late lumen loss at 13 months. Stent thrombosis ( ST) served as the safety endpoint. Dual anti-platelet therapy ( DAPT) was prescribed for 6 months. Results Clinical follow-up for 12 months and repeat angiography at 13 months were available in 100% and >90% of patients, respectively. The ISR and in-stent late loss were significantly different between the Excel (3.1%, 0.09 ± 0.11 mm) and the Dual DES (19.5%, 0.36 ± 0.32 mm, P < 0.001, P < 0.001, respectively) groups. The TVR (3.5%) in the Excel group was significantly less than in the Dual DES group (13.9%, P = 0.001). The ST rate beyond 12 months in the Dual DES group was 0%, and this was 1.2% in the Excel group ( P = 0.499). Conclusions The Excel stent was statistically superior to the Dual DES in terms of restenosis, late loss, and TVR for long lesions. [ABSTRACT FROM AUTHOR]

Background and objectives: A large number of clinical studies have well demonstrated that the loss-of-function variant allele CYP2C19*2 is associated with attenuated response to clopidogrel and increased risk of developing stent thrombosis (ST) in white or black patients with stenting. However, similar association studies on the effect of the CYP2C19*2 and *3 variants on maximum platelet aggregation (MPA) and the risk of cardiovascular events are currently unavailable for the Chinese patients. This work was aimed at assessing the impact of the CYP2C19 *2 and *3 variants on the antiplatelet effects and adverse cardiovascular events in clopidogrel-treated Chinese patients undergoing percutaneous coronary intervention (PCI). Methods: The study population consisted of 617 patients undergoing PCI. Genotypes were determined using MALDI/TOF-MS. MPA was measured by light transmittance aggregometry. The clinical end-point was the 1-year incidence of adverse cardiovascular events, including ST. Results: Carriers of CYP2C19 heterozygous (*1/*2, or *1/*3; n = 278) and mutant homozygous (*2/*2, *2/*3, or *3/*3, n = 80) genotypes had significantly higher MPA values than noncarriers (*1/*1; n = 259; P = 0.036 and 0.007 respectively). Moreover, the presence of the CYP2C19*2 or *3 mutant allele was significantly associated with an increased risk of developing ST, with the higher risk of ST being seen in patients homozygous for the CYP2C19*2 or *3 variant allele than in noncarriers (OR, 13.58; 95% CI, 1.49-123.31; P = 0.012). Furthermore, multivariate analysis revealed an independent association of the presence of CYP2C19*2 and/or *3 variant alleles with greater MPA values ( P = 0.001) and increased risk of ST (OR, 11.67; 95% CI, 1.21-78.83; P = 0.022). However, there was no significant influence of CYP2C19*2 and *3 on the risk of developing other adverse cardiovascular events. Conclusions: Carriage of the loss-of-function genetic variants CYP2C19*2 and *3 is significantly associated with attenuated platelet response to clopidogrel and an increased risk of ST in Chinese patients treated with stenting. [ABSTRACT FROM AUTHOR]