Na+/K+-ATPase is a novel target to treat anxiety / 中国药理学与毒理学杂志

OBJECTIVE Na+/K+-ATPase(NKA)is a large membrane protein expressed universally in all cells.It is indispensable for the maintenance of ionic gradient.We previously reported that the dysfunction of this pump in neurons and astrocytes contributes to stroke and neurodegenerative diseases,respectively.However,its roles in the microglia and stress-related diseases are still unclear.METHODS Two classical models,chronic restraint stress(CRS)model and electronic foot shock(ES)model,were used to study the pathogenesis of anxi-ety in either NKAα1 global knockout(NKAα1 GKO)mice or NKA α1 conditional knockout(NKAα1 CKO)mice.Behavioral tests like open-field test,elevated plus maze,Morris water maze,novel object recognition test and gait imaging test were performed.A variety of molecular bio-logical methods were employed,including RNA sequenc-ing(RNA-seq)analyses,immunofluorescence and elec-trophysiological recordings etc.RESULTS NKAα1 defi-ciency had a broad impact on physical stress-induced anxiety-like behavior,but failed to exacerbate CRS induced memory deficits.Electrophysiology experiment showed that NKAα1 GKO and NKAα1 CKO mice exhibit-ed neuronal hyperexcitability under chronic stress.The underlying mechanisms may involve neuroinflammation,as NKAα1 deficiency exacerbated stress-induced microg-lia activation in vivo.Similarly,inhibition or downregula-tion of NKA α 1 aggravated LPS + ATP-induced inflam-mation in vitro.DR5-12D,a monoclonal antibody against the DR-region of NKAa1,improved stress-induced anxiety-like behavior through amelioration of the neuronal hyper-excitability and neurogenesis deficit in the ventral hippo-campus of mice.CONCLUSION NKA is closely related to neuroinflammation in microglia and DR-region of NKA a1 subunit may serve as a novel target to treat stress-induced anxiety.

ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

Lung transplantation for chronic thromboembolic pulmonary hypertension: a report of 6 cases / 中华器官移植杂志

Objective To investigate the selection of recipients,operative technique,and perioperative management of lung transplantation for chronic thromboembolic pulmonary hypertension.Methods This article reviews the clinical data of 6 patients with chronic thromboembolic pulmonary hypertension receiving lung transplantation from January 2012 to June 2016.From January 2012 to June 2016,6 patients with chronic thromboembolic pulmonary hypertension underwent lung transplantation at Department of Thoracic Surgery,Affiliated Wuxi People's Hospital,Nanjing Medical University.There were 4 male and 2 female patients aged from 34 to 59 years.Chest enhancement of CT or CTPA in 6 patients prior to transplantation suggests a different degree of pulmonary embolism.The mean pulmonary artery pressure (mPAP) was＞30 mmHg,NYHA 11Ⅰ or Ⅳ.Four patients received bilateral sequence lung transplantation (BSLT) under extracorporeal membrane oxygenation (ECMO) support.Two patients received single lung transplantation (SLT).We analyzed the differences of oxygenation index,pulmonary systolic pressure,pulmonary artery diastolic pressure,mean pulmonary arterial pressure,and central venous pressure before and after treatment.Using paired t test to compare these indicators,P＜0.05 was considered statistically significant.Results The oxygenation index increased from (195 ± 85) to (440 ± 140) mmHg after treatment,the difference was statistically significant (P＜0.05).the The systolic pressure of pulmonary artery was decreased from (108 ± 28) mmHg to (56 ± 16) mmHg,and the difference was statistically significant (P＜0.05).the The diastolic pressure of pulmonary artery was decreased from (72 ± 18) mmHg to (25 ± 10) mmHg,and the difference was statistically significant (P＜0.05).the The mean pulmonary artery pressure was decreased from (84 ± 27) mmHg to (36 ± 10) mmHg,and the difference was statistically significant (P＜0.05).the The central venous pressure was decreased from (17.5 ± 4.5) mmHg to (8.5 ± 1.5) mmHg,and the difference was statistically significant (P＜0.05).Finally,5 patients were discharged from the hospital,and the pulmonary valve? functioned? well.1 patients died of shock and systemic failure 3 days after operation.Conclusion Lung transplantation is effective in the treatment of chronic thromboembolic pulmonary hypertension,and long-term survival requires further investigations.

Comparative study of right to left ventricular volume ratio measured on chest CT and echocardiography in the diagnosis of pulmonary artery pressure before lung transplantation / 中华器官移植杂志

Objective To investigate the correlation of right ventricular (RV) to left ventricular (LV) volume ratio (RVv/LVv) measured by chest CT with pulmonary arterial pressure estimated by echocardiography before lung transplantation.Methods We reviewed 104 cases of lung transplant.According to the mean pulmonary arterial pressure (mPAP) exceeding 25 mmHg by right heart catheterization,hypertensive group (n =74) and normotensive group (n =30) were set up.Risk factors were assessed individually and adjusted for confounding by a multivariable logistic regression analysis.The area under the curve (AUC) for predicting pulmonary hypertension on chest CT and echocardiography was calculated.Results RVv/LVv and echocardiography-derived ptlmonary arterial systolic pressure (PASP) were significantly different between the two groups (P ＜ 0.05).In the hypertensive group,there was strong correlation between the RVv/LVv and PASP from catheterization (R =0.82,P＜0.001),also between the P ASP from echocardiography and catheterization (R =0.60,P＜ 0.001).The ROC curve displayed that with 0.85 as the cutoff for RVv/LVv,the sensmitivity,specificity and accuracy rate for predicting mPAP over 25 mmHg were 87.5％,91.8％ and 90.9％,respectively.The ROC curve also displayed that based upon an echocardiography-derived PASP of 35 mmHg as the cutoff point,the sensitivity,specificity and accuracy rate for predicting mPAP over 25 mmHg were 91.2％,90.8％ and 88.4％,respectively.Conclusion RV/LV volume ratios on chest CT and echocardiographic evaluation correlate well with PASP assessed by right heart catheterization and can be used to predict pulmonary hypertension with high sensitivity and specificity.