Molecular mechanism of HDAC6-mediated pyroptosis in neurological function recovery after cardiopulmonary resuscitation in rats.

Brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is the leading cause of neurological dysfunction and death. This study aimed to explore the mechanism of histone deacetylase 6 (HDAC6) in neurofunctional recovery following CA/CPR in rats. A rat model was established by CA/CPR treatment. Adenovirus-packaged sh-HDAC6 was injected into the tail vein. To evaluate the neurofunction of rats, survival time, neurofunctional scores, serum NSE/S100B, and brain water content were measured and Morris water maze test was performed. HDAC6, microRNA (miR)-138-5p, Nod-like receptor protein 3 (NLRP3), and pyroptotic factor levels were determined by real-time quantitative polymerase chain reaction or Western blot assay. HDAC6 and H3K9ac enrichment on miR-138-5p promoter were examined by chromatin immunoprecipitation. miR-138-5p-NLRP3 binding was analyzed by dual-luciferase reporter assay. NLRP3 inflammasome was activated with nigericin sodium salt. After CPR treatment, HDAC6 was highly expressed, while miR-138-5p was downregulated. HDAC6 downregulation improved neurofunction and reduced pyroptosis. HDAC6 enrichment on the miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p, and promoting NLRP3-mediated pyroptosis. Downregulating miR-138-5p partially reversed the protective effect of HDAC6 inhibition after CPR. In Conclusion, HDAC6 enrichment on miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p expression and promoting NLRP3-mediated pyroptosis, worsening neurological dysfunction in rats after CPR.

A young woman presenting with dyspnoea and diffuse T-wave inversions: a case report.

Background: T-wave inversions on electrocardiograms (ECGs) indicate a variety of conditions, such as coronary artery disease, myocarditis, and cardiomyopathy. Pulmonary artery stenosis (PAS) and pulmonary hypertension (PH) may cause right ventricular enlargement and ischaemia, which are reflected as T-wave inversions on ECGs. Continuous ECG monitoring is crucial for detecting dynamic changes indicative of PAS progression and reversal in right heart remodelling. Case summary: This report presents the case of a young woman who experienced exertional dyspnoea for 5 years with ECG findings showing T-wave inversions across multiple leads. The patient was diagnosed with PAS and PH caused by Takayasu arteritis (TA). Following three successful balloon pulmonary angioplasty sessions, the patient exhibited significant clinical improvement, including the remission of PAS and PH. Throughout a 59-month cumulative follow-up period, the sustained effectiveness of the treatment was evidenced by the regression of right heart remodelling, as manifested in the normalization of the initially inverted T-waves on the ECG. Discussion: Electrocardiogram changes, including right axis deviation, right bundle branch block, a deep S wave in lead I (R/S < 1), and a prominent R wave in lead aVR (R/Q > 1), have been termed PAS syndrome, often linked to TA-associated PAS, especially in young East Asian females. Early diagnosis is crucial but challenging due to atypical symptoms. The non-invasive ECG is vital for detection, with balloon pulmonary angioplasty serving as an effective treatment for TA-induced PAS when surgery is not an option, improving outcomes and potentially reversing right heart remodelling.

Machine Learning Based on Computed Tomography Pulmonary Angiography in Evaluating Pulmonary Artery Pressure in Patients with Pulmonary Hypertension.

BACKGROUND: Right heart catheterization is the gold standard for evaluating hemodynamic parameters of pulmonary circulation, especially pulmonary artery pressure (PAP) for diagnosis of pulmonary hypertension (PH). However, the invasive and costly nature of RHC limits its widespread application in daily practice. PURPOSE: To develop a fully automatic framework for PAP assessment via machine learning based on computed tomography pulmonary angiography (CTPA). MATERIALS AND METHODS: A machine learning model was developed to automatically extract morphological features of pulmonary artery and the heart on CTPA cases collected between June 2017 and July 2021 based on a single center experience. Patients with PH received CTPA and RHC examinations within 1 week. The eight substructures of pulmonary artery and heart were automatically segmented through our proposed segmentation framework. Eighty percent of patients were used for the training data set and twenty percent for the independent testing data set. PAP parameters, including mPAP, sPAP, dPAP, and TPR, were defined as ground-truth. A regression model was built to predict PAP parameters and a classification model to separate patients through mPAP and sPAP with cut-off values of 40 mm Hg and 55 mm Hg in PH patients, respectively. The performances of the regression model and the classification model were evaluated by analyzing the intraclass correlation coefficient (ICC) and the area under the receiver operating characteristic curve (AUC). RESULTS: Study participants included 55 patients with PH (men 13; age 47.75 ± 14.87 years). The average dice score for segmentation increased from 87.3% ± 2.9 to 88.2% ± 2.9 through proposed segmentation framework. After features extraction, some of the AI automatic extractions (AAd, RVd, LAd, and RPAd) achieved good consistency with the manual measurements. The differences between them were not statistically significant (t = 1.222, p = 0.227; t = -0.347, p = 0.730; t = 0.484, p = 0.630; t = -0.320, p = 0.750, respectively). The Spearman test was used to find key features which are highly correlated with PAP parameters. Correlations between pulmonary artery pressure and CTPA features show a high correlation between mPAP and LAd, LVd, LAa (r = 0.333, p = 0.012; r = -0.400, p = 0.002; r = -0.208, p = 0.123; r = -0.470, p = 0.000; respectively). The ICC between the output of the regression model and the ground-truth from RHC of mPAP, sPAP, and dPAP were 0.934, 0.903, and 0.981, respectively. The AUC of the receiver operating characteristic curve of the classification model of mPAP and sPAP were 0.911 and 0.833. CONCLUSIONS: The proposed machine learning framework on CTPA enables accurate segmentation of pulmonary artery and heart and automatic assessment of the PAP parameters and has the ability to accurately distinguish different PH patients with mPAP and sPAP. Results of this study may provide additional risk stratification indicators in the future with non-invasive CTPA data.

Association between splenectomy and chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis.

OBJECTIVE: Whether splenectomy increases the risk of chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We conducted a systematic review and meta-analysis to explore the association between splenectomy and CTEPH. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase and Cochrane Library databases. METHODS: Two authors independently searched and extracted the data. The Newcastle-Ottawa Scale and the Strengthening the Reporting of Observational Studies in Epidemiology guidelines were used to assess the quality of the included studies, and each quality item was graded as low risk or high risk. A random-effects model was used to calculate different effective values. RESULTS: In total, 8 trials involving 6183 participants fulfilled the inclusion criteria. The overall pooled crude prevalence of splenectomy was 4.0% (95% CI 0.03 to 0.06, I2=71.5%, p<0.001) in patients with CTEPH. Subgroup analysis showed a statistically significant high incidence of splenectomy in patients with CTEPH (OR=2.94, 95% CI 1.62 to 5.33, I2=0.0%, p<0.001) compared with patients with pulmonary arterial hypertension. There was a significantly high incidence of splenectomy in patients with CTEPH (OR=5.59, 95% CI 2.12 to 14.74, I2=0.0%, p<0.001) compared with patients with thromboembolism disease (venous thromboembolism or pulmonary embolism). CONCLUSION: The prevalence of splenectomy in patients with CTEPH was 4.0% and CTEPH might be associated with splenectomy. However, high-quality prospective trials are needed. PROSPERO REGISTRATION NUMBER: CRD42020137591.

A rare case of severe right heart failure due to pulmonary artery lymphomatoid granulomatosis.

Lymphomatoid granulomatosis is a rare, vascular-centric, and vessel-destroying lymphoproliferative disease that hardly involves the pulmonary arteries. Herein, we report a case with severe right heart failure and pulmonary arterial stenosis caused by pulmonary artery lymphomatoid granulomatosis. This case was diagnosed by percutaneous transluminal pulmonary artery biopsy and was effectively treated with stent implantation and steroid administration.

lncRNA HAND2­AS1 mediates the downregulation of ROCK2 in hepatocellular carcinoma and inhibits cancer cell proliferation, migration and invasion.

Long noncoding (lnc)RNA HAND2­AS1 inhibits the development of several human malignancies. The role of HAND2­AS1 was investigated in hepatocellular carcinoma (HCC). It was found that levels of HAND2­AS1 in serum were significantly lower, while serum levels of Rho­associated protein kinase 2 (ROCK2) in HCC patients were significantly increased compared with hepatitis B (HB) patients and healthy controls. Decreased HAND2­AS1 levels distinguished HCC patients but not HB patients from healthy controls. A significant negative correlation between HAND2­AS1 and ROCK2 was found in HCC patients but not in HB patients or healthy controls. HAND2­AS1 overexpression inhibited, while ROCK2 overexpression promoted HCC cell migration, proliferation and invasion. HAND2­AS1 overexpression led to downregulated ROCK2 expression. ROCK2 overexpression did not significantly affect ROCK2 expression but attenuated the inhibitory effects of HAND2­AS1 overexpression. It was therefore concluded that HAND2­AS1 might mediate the downregulation of ROCK2 in HCC to inhibit cancer cell migration, proliferation and invasion.

PF4 antagonizes retinal neovascularization via inhibiting PRAS40 phosphorylation in a mouse model of oxygen-induced retinopathy.

Retinal neovascularization (RNV) is a common pathology of blinding proliferative retinopathies. The current treatments to RNV, however, are hindered by limited efficacy, side effects, and drug resistance. A naturally-occurring cytokine in retina that is amicable to immune system and possesses robust anti-neovascular function would facilitate to overcome the hurdles. In this study, retinas from a mouse model of oxygen-induced retinopathy (OIR) underwent a protein array to screen the naturally-occurring cytokines that may antagonize RNV. Among the 62 angiogenesis-associated cytokines, platelet factor 4 (Pf4) stood out with the most prominent upregulation and statistical significance. Moreover, an intravitreal injection of mouse Pf4 demonstrated dramatic anti-vaso-obliteration and anti-neovascularization effects dose dependently in the OIR model; whereas human PF4 inhibited the proliferation, migration, and tubulogenesis of monkey retinal vascular endothelial cells treated with VEGF and TNF-α. These previously undescribed angiostatic effects of PF4 in OIR retinas and retinal vascular endothelial cells support translation of this naturally-occurring chemokine into a therapeutic modality to RNV supplementary to the anti-VEGFs. Mechanistically, a phosphorylation array and western blots indicated that downregulation of proline-rich Akt substrate of 40 kDa (Pras40) and its phosphorylation were necessary for Pf4's anti-neovascular effects in the OIR retinas. Indeed, overexpression of the wildtype Pras40 and the mutant version with deficient phosphorylation abolished and mimicked the Pf4's angiostatic effects in the OIR retinas, respectively. The similar effects were also observed in vitro. This study, for the first time, links PF4's anti-RNV function to an intracellular signaling molecule PRAS40 and its phosphorylation.

Acute myocardial infarction and transient elevated anticardiolipin antibody in a young adult with possible familial hypercholesterolemia: a case report : Anticardiolipin antibody and myocardial infarction.

BACKGROUND: Familial hypercholesterolemia (FH) can lead to premature coronary heart disease. Anticardiolipin antibody may be a contributor for thrombosis. Here, we report an adult with possible FH suffered from premature myocardial infarction that may be triggered by transient increased anticardiolipin antibody. CASE PRESENTATION: A 29-year-old male had presented with a history of 2-h chest pain and numbness of left upper arm before 5 days. The electrocardiogram (ECG) had demonstrated inferior wall myocardial infarction (MI). Five days later he was admitted to our hospital and diagnosed as acute MI and possible FH (premature coronary heart disease, low density lipoprotein cholesterol of 5.90 mmol/L) with increased anticardiolipin antibody (up to 120 RU/ml). Other auto-antibodies including ß2-glicoprotein antibodies IgM, IgA, IgG, lupus anticoagulant (LA), antinuclear antibodies, anti-myocardial antibody were normal. Coronary artery angiography (CAG) showed right coronary artery was total occlusion from the middle segment. Then he underwent percutaneous coronary intervention with a stent. Four days later, he was discharged with complete recovery. CAG showed intra-stent restenosis and anticardiolipin antibody level was normal and the patient had no any symptoms at 6-month follow-up. CONCLUSIONS: Transient elevated anticardiolipin antibody may be a trigger or biomarker of cardiac thrombotic events in younger atherosclerotic patients.

Autologous bone marrow stem cell therapy for patients undergoing coronary artery bypass grafting: A meta-analysis of 14 randomized controlled trials.

Autologous bone marrow stem cell (BMSC) therapy is a novel option for regenerative therapy in patients with ischemic heart disease. The aim of the present meta-analysis was to evaluate the effectiveness of BMSCs combined with coronary artery bypass grafting (CABG). The PubMed, Cochrane Library, EMBASE and Web of Science databases were searched from inception to November 22, 2017 for randomized controlled trials on BMSC therapy combined with CABG. Finally, 14 trials with a total of 596 participants were included. Data were analyzed using a random-effects model. Compared with the control group, the BMSC therapy group exhibited an improvement in the left ventricular (LV) ejection fraction from baseline to follow-up [mean difference (MD)=4.36%; 95% confidence interval (CI): 1.90-6.81%; P<0.01]. Analysis of the pooled results revealed non-significant differences in the LV end-diastolic volume (MD=-6.27 ml; 95% CI: -22.34 to 9.80 ml; P=0.44), LV end-diastolic volume index (MD=-15.11 ml/m2; 95% CI: -31.53 to 1.30 ml/m2; P=0.07), LV end-systolic volume (MD=-11.52 ml; 95% CI: -26.97 to 3.93 ml; P=0.14) and LV end-systolic volume index (MD=-16.56 ml/m2; 95% CI: -37.75 to 4.63 ml/m2; P=0.13) between the BMSC and CABG alone groups. Therefore, autologous BMSC therapy for patients undergoing CABG appears to be associated with an improvement in LV function compared with CABG alone.

Exploring the role of programmed cell death protein 1 and its ligand 1 in eye diseases.

Programmed death receptor-1 (PD-1) and its ligand, PD-L1, as negative co-stimulatory molecules, are indispensable for regulating both physiological and pathological immune responses. The PD-1/PD-L1-mediated signaling pathway has been studied extensively in cancer research and has become a hotspot for biopharmaceuticals and immunotherapy. Furthermore, monoclonal antibodies to PD-1 have just been approved by the US Food and Drug Administration to treat certain types of malignancies. Recent research has unveiled a close association between the PD-1/PD-L1 system and eye diseases. This review describes the expression and physiological functions of PD-1 and its ligand in ocular tissues and summarizes the pathogenic, regulatory, and therapeutic roles of PD-1/PD-L1 system in eye diseases, including uveal melanoma, autoimmune uveitis, autoimmune dry eye, sympathetic ophthalmia, Graves' ophthalmopathy, diabetic retinopathy, herpes simplex keratitis, and trachoma, with the intent of highlighting the potential of PD-1/PD-L1 as novel therapeutic targets or biomarkers for these ocular diseases.

Α-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R.

BACKGROUND/AIMS: Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). METHODS: Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with α-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of α-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the α-MSH's anti-hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating α-MSH's protection. RESULTS: Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by α-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in α-MSH-treated diabetic retinas; scotopic ERG suggested partial rescue of functional defects by α-MSH in diabetic retinas; and H&E staining revealed significantly increased thickness of all layers in α-MSH-treated diabetic retinas. Mechanistically, α-MSH corrected aberrant transcript and protein expression of pro-inflammatory factor and tight junction genes in the diseased retinas; moreover, it prevented abnormal changes in TEER and permeability in HG-stimulated RF6A cells, and this anti-hyperpermeability was abolished by a universal MCR blocker or an antagonist specific to MC4R. CONCLUSIONS: This study showed previously undescribed protective effects of α-MSH on inhibiting BRB breakdown and vascular leakage, improving electrophysiological functions and morphology in early diabetic retinas, which may be due to its down-regulating pro-inflammatory factors and augmenting tight junctions. α-MSH acts predominantly on MC4R to antagonize hyperpermeability in retinal microvessel endothelial cells.

Decoding Noncoding RNAs: Role of MicroRNAs and Long Noncoding RNAs in Ocular Neovascularization.

Ocular neovascularization is a pathological sequel of multiple eye diseases. Based on the anatomical site into which the abnormal neovessels grow, ocular neovascularization can be categorized into corneal neovascularization, choroidal neovascularization, and retinal neovascularization. Each category is intractable, and may lead to blindness if not appropriately treated. However, the current therapeutic modalities, including laser photocoagulation, vitrectomy surgery, and anti-VEGF drugs, raise concerns due to limited efficacy, damage on retinal parenchyma and vasculature, and the patients' unresponsiveness to the treatments. Therefore, the in-depth study on pathogenesis of and the search for novel therapeutic targets to the ocular neovascularization are needed. During the last 10 years or so, a large number of literatures have emerged indicating a critical role of noncoding RNAs, particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), in the pathogenesis and regulation of the ocular neovascularization. This review summarizes the current understanding of the biosynthesis and functions of the miRNAs and lncRNAs, the regulation of the miRNAs and lncRNAs in neovascular eye diseases, as well as the roles of these noncoding RNAs in the disease models of ocular neovascularization, in the hope that it could provide clues for the pathogenesis of and molecular targets to the ocular neovascularization.

[Study on mechanisms and myocardial protective effect of Qishen Yiqi dropping pills on rats with myocardial infarction].

OBJECTIVE: To approach the mechanisms and myocardial protective effect of Qishen Yiqi dropping pills on rats with myocardial infarction. METHODS: Sixty clean healthy male Sprague-Dawley (SD) rats were randomly divided into sham operation group, model group and observation group (each n = 20). The rat model of acute myocardial infarction (AMI) was established by ligation of left anterior descent (LAD) branch of coronary artery. After modeling, the rats in observation group were given 0.135 g/kg of Qishen Yiqi dropping pills, and sham operation group and model group were administered the same amount of normal saline, once a day for consecutive 28 days. At the end of treatment, the levels of serum inflammatory factors of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured by enzyme linked immunosorbent assay (ELISA); the changes of the indexes of hemodynamic [left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximal rate of increase/decrease in left ventricular pressure (±dp/dt max)], the ratio of the heart weight/body weight, and the ratio of the left ventricular weight/heart weight (LVW/HW), the myocardial infarction area, myocardial histopathological changes were observed in the three groups; myocardial tissues inflammatory related factors [the mRNA and protein expressions of cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX)], and the expression levels of transforming growth factor-ß (TGF-ß)/Smads signal transduction pathway related protein (TGF-ß1, Smad2/3, Collagen I, Collagen III) and cell apoptosis related factors (Bcl-2, Bax) protein were measured. RESULTS: Compared with the sham operation group, levels of serum inflammatory factors, the index of LVEDP, the ratio of the heart weight/body weight, LVW/HW, myocardial infarction area, the mRNA and protein expression levels of inflammatory factors in myocardium, the expression levels of TGF-ß/Smads signal transduction pathway related protein and the cell apoptosis related factors protein in model group were all significantly elevated, while LVSP and ±dp/dt max were obviously decreased in model group. Compared with the model group, the levels of inflammatory factor in serum [LTB4 (ng/L): 370.11±46.98 vs. 633.23±83.37, PGE2 (ng/L): 48.75±26.35 vs. 131.25±29.75, TNF-α (µg/L): 177.28±22.65 vs. 248.47±16.21, IL-6 (µg/L): 493.22±165.99 vs. 638.41±191.66], LVEDP [mmHg (1 mmHg = 0.133 kPa): -2.03±2.98 vs. 7.03±1.39], the ratio of the heart weight/body weight [(6.53±0.11)% vs. (7.14±0.24)%], LVW/HW (0.26±0.01 vs. 0.32±0.02), myocardial infarction area [(27.21±2.87)% vs. (44.98±1.52)%], mRNA and protein expression of myocardial inflammatory factors, the expression of TGF-ß/Smads signal transduction pathway related protein, and the protein expression of Bax were all significantly decreased in observation group (all P < 0.05), LVSP (mmHg: 129.01±11.93 vs. 108.11±12.69), the +dp/dt max (mmHg/s: 3 101.3±378.6 vs. 2 105.3±245.9), the -dp/dt max (mmHg/s: 2 612.4±249.7 vs. 1 654.4±188.1), while the protein expression of Bcl-2 in observation group were obviously increased (all P < 0.05). It was demonstrated by hematoxylin-eosin (HE) staining that there were no obvious pathological changes in the sham operation group; obvious infiltration of inflammatory factors in myocardium was shown in model group; pathological changes in the observation group were significantly improved as compared with those in the model group. It was shown by Masson staining that there were slight hyperplasia of myocardial fibers and no obvious pathological changes in the sham operation group. Severe collagen hyperplasia was found in model group, and the degree of fibrosis in the observation group was significantly improved. CONCLUSIONS: Qishen Yiqi dropping pills can reduce the degree of myocardial fibrosis and inhibit the ventricular remodeling via TGF-ß/Smads signal transduction pathway. The dropping pills can also suppress the release of inflammatory factors by reducing cPLA2 to decrease the inflammatory response and inhibit apoptosis and alleviate myocardial injury by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax.

TSH inhibits SERCA2a and the PKA/PLN pathway in rat cardiomyocytes.

Elevated thyroid-stimulating hormone (TSH) levels often accompany impaired LV diastolic function and subtle systolic dysfunction in subclinical hypothyroidism (sHT). These cardiac dysfunctions are characterized by increases in mean aortic acceleration and pre-ejection/ejection time ratios. To explore the mechanism underlying these pathologies, we investigated the effects of TSH on sarcoplasmic reticulum calcium ATPase (SERCA2a) activity and expression in neonatal rat cardiomyocytes. TSH inhibited SERCA2a activity and expression by binding to TSH receptors in cardiomyocyte membranes and inhibiting the protein kinase A/phoshpolamban (PKA/PLN) signaling pathway. These results suggest that increases in serum TSH levels contribute to the development of cardiac diastolic and systolic dysfunction.

Netrin-1 prevents the development of cardiac hypertrophy and heart failure.

The aim of the present study was to examine whether netrin-1 is involved in the development of cardiac hypertrophy, induced by pressure overload. For this investigation, thoracic transverse aortic constriction (TAC) was performed in mice. A total of 18 mice were divided into three groups (n=6 per group): Sham, TAC and TAC + recombinant netrin-1. Neonatal rat cardiomyocytes were stimulated with endothelin-1 (ET-1), and samples were collected to examine the expression levels of netrin­1 by western blot analysis and the mRNA expression of A­type natriuretic peptide by reverse transcription­quantitative polymerase chain reaction. It was found that the expression of netrin­1 was decreased in the TAC mice and in the neonatal rat cardiomyocytes in response to ET­1 stimulation. Netrin­1 eliminated ventricular remodeling, cardiac dysfunction and DNA damage during pressure overload. Furthermore, analysis of the signaling events indicated that netrin­1­mediated protection against cardiac hypertrophy was attributed to interruption of the activation of mitogen­activated protein kinase kinase (MEK) kinase­1 (K1)­dependent MEK­extracellular signal­regulated protein kinase 1/2 (ERK1/2) and c­Jun N­terminal kinase 1/2 (JNK1/2). Therefore, netrin­1 prevented cardiac hypertrophy and heart failure through the negative regulation of the MEKK1-dependent MEK­ERK1/2 and JNK1/2 signaling pathways.

Differences in Akt signaling and metabolism gene expression in the right heart, intraventricular septum and left heart of rodents.

The right heart is functionally and structurally different from the left heart; however, potential differences in Akt signaling and the expression of metabolic genes between the right heart and left heart in different rodents are still unknown. Using Western blotting and real time quantification polymerase chain reaction, we measured the levels of total Akt, phosphorylated Akt and its downstream targets as well as metabolism genes including glucose transporter 1, glucose transporter 4 (GLUT4), peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor γ, peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and pyruvate dehydrogenase lipoamide kinase isozyme 4. We found that phosphorylated Akt and proline-rich Akt substrate 40 levels were significantly increased in the RV compared with the LV in rats but only had an increased trend in mice. Correspondingly, GLUT4 was significantly increased in the RV compared with the LV both in mice and rats. PGC-1α was significantly increased in the RV compared with the LV in mice but only had an increased trend in rats. Moreover, Akt signaling activity and metabolism genes' expression in the IVS were similar to the RV in mice but to the LV in rats. There were some differences in the activity of Akt signaling and in the levels of metabolism genes among the right ventricle, interventricular septum and left ventricle. Also, the diversity of activity of Akt and metabolism genes between the right ventricle and left ventricle are different between rats and mice. In conclusion, the activity of Akt signaling and the levels of metabolism genes are different among the right ventricle, interventricular septum and left ventricle providing some potential clues for exploring the roles of Akt signaling and cardiac metabolisms in different parts of the heart. Additionally, the differences in Akt activity and metabolism genes' levels between the right and left ventricles are different between mice and rats, to which we should pay attention when using different animal model in heart study.

Success rate and safety of coronary angiography and angioplasty via radial artery approach among a Chinese population.

OBJECTIVE: To find out the safety and success rate of transradial coronary angiography and angioplasty among a Chinese population. DESIGN: This was a prospective study performed on 2845 consecutive patients in a single interventional center at the first affiliated hospital, Nanjing Medical University, in Nanjing from August 2012 to July 2013. Allen's test was carried out on all patients who were involved in the study. Patients with abnormal Allen's test, cardiogenic shock, those on hemodialysis, and foreigners were excluded from the study. Our goal was to determine the efficacy and complications of coronary angiography (CAG) and percutaneous coronary intervention (PCI) through the radial approach in our local population. RESULTS: The mean age of our patients was 64 ± 7.5 years with 1628 males (57.2%) and 1217 females (42.8%). A total of 1537 patients (54.0%) were hypertensive, while 501 patients (17.6%) were diabetic. Six patients (0.002%) had previous coronary artery bypass surgery. None of our patients had any bleeding disorder. A total of 1416 CAGs (49.8%) and 1429 PCIs (50.2%) were performed. The success rate was 97.6% for CAG and 96.3% for PCI. Seven patients (0.25%) had minor hematoma and 49 patients (1.7%) had reduced radial pulse 3-4 hours post procedure. CONCLUSION: Transradial coronary intervention is safe and practical. It should be favored over femoral artery as an initial access point.

Phosphoinositide-dependent kinase 1 and mTORC2 synergistically maintain postnatal heart growth and heart function in mice.

The protein kinase Akt plays a critical role in heart function and is activated by phosphorylation of threonine 308 (T308) and serine 473 (S473). While phosphoinositide-dependent kinase 1 (PDK1) is responsible for Akt T308 phosphorylation, the identities of the kinases for Akt S473 phosphorylation in the heart remain controversial. Here, we disrupted mTOR complex 2 (mTORC2) through deletion of Rictor in the heart and found normal heart growth and function. Rictor deletion caused significant reduction of Akt S473 phosphorylation but enhanced Akt T308 phosphorylation, suggesting that a high level of Akt T308 phosphorylation maintains Akt activity and heart function. Deletion of Pdk1 in the heart caused significantly enhanced Akt S473 phosphorylation that was suppressed by removal of Rictor, leading to worsened dilated cardiomyopathy (DCM) and accelerated heart failure in Pdk1-deficient mice. In addition, we found that increasing Akt S473 phosphorylation through deletion of Pten or chemical inhibition of PTEN reversed DCM and heart failure in Pdk1-deficient mice. Investigation of heart samples from human DCM patients revealed changes similar to those in the mouse models. These results demonstrated that PDK1 and mTORC2 synergistically promote postnatal heart growth and maintain heart function in postnatal mice.