LncRNA CASC2 inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation and migration by regulating the miR-222/ING5 axis.

BACKGROUND: Pulmonary arterial hypertension (PAH) is often characterized by cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). LncRNA cancer susceptibility candidate 2 (CASC2) has been revealed to be involved in PASMC injury in hypoxia-induced pulmonary hypertension. However, the exact molecular mechanisms whereby CASC2 regulates PASMC proliferation and migration are still incompletely understood. METHODS: The expression levels of CASC2, miR-222 and inhibitor of growth 5 (ING5) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot, respectively. Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8) assay. Wound healing assay was used to analyze cell migration ability. The relationship between miR-222 and CASC2 or ING5 was confirmed using bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: CASC2 was down-regulated in hypoxia-induced PASMCs in a dose- and time-dependent manner. Functional experiments showed that CASC2 overexpression could reverse hypoxia-induced proliferation and migration of PASMCs. Bioinformatics analysis indicated that CASC2 acted as a competing endogenous RNA of miR-222, thereby regulating the expression of ING5, the downstream target of miR-222, in PASMCs. In addition, rescue assay suggested that the inhibition mediated by CASC2 of hypoxia-induced PASMC proliferation and migration could be attenuated by miR-222 inhibition or ING5 overexpression. CONCLUSION: CASC2 attenuated hypoxia-induced PASMC proliferation and migration by regulating the miR-222/ING5 axis to prevent vascular remodeling and the development of PAH, providing a novel insight and therapeutic strategy for hypoxia-induced PAH.

HTLV-1 basic leucine zipper factor downregulates cyclin D1 expression via interactions with NF-κB.

Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus. It can cause adult T cell leukemia (ATL) and other diseases. The HTLV-1 basic leucine zipper (bZIP) factor (HBZ), which is encoded by the minus-strand of the provirus, is expressed in all cases of ATL and involved in T cell proliferation. However, the exact mechanism underlying its growth-promoting activity is poorly understood. Herein, we demonstrated that HBZ suppressed cyclin D1 expression by inhibiting the nuclear factor (NF)-κB signaling pathway. Among the potential mechanisms of cyclin D1 inhibition mediated by HBZ, we found that HBZ suppressed cyclin D1 promoter activity. Luciferase assay analysis revealed that HBZ repressed cyclin D1 promoter activity by suppressing NF-κB­driven transcription mediated by the p65 subunit. Using an immunoprecipitation assay, we found that HBZ could bind to p65, but not p50. Finally, we showed that HBZ selectively interacted with p65 via its AD+bZIP domains. By suppressing cyclin D1 expression, HBZ can alter cell cycle progression of HTLV-1-infected cells, which may be critical for oncogenesis.

Usefulness of a Combination of Interatrial Block and a High CHADS2 Score to Predict New Onset Atrial Fibrillation.

Interatrial block (IAB) is associated with an increased risk of atrial fibrillation (AF). The aim of this retrospective study was to investigate the association of a combination of IAB and the CHADS2 score, an AF-related risk score for ischemic stroke, with new onset AF in patients in sinus rhythm. A total of 1,571 patients (803 males, 768 females; mean age: 58 ± 16 years) were included in this study. IAB was defined as a P-wave duration > 120 ms in the 12-lead electrocardiogram, and a high CHADS2 score as ≥ 2 points. During the mean follow-up period of 4.8 ± 0.7 years, new onset AF occurred in 122 patients (16.1 per 1,000 patient-years). The incidence of new onset AF was 4.0 per 1,000 patient-years in patients with no IAB and a low CHADS2 score, and 44.0 per 1,000 patient-years in patients with IAB and a high CHADS2 score. In multivariate Cox regression analysis, the hazard ratio for IAB and a high CHADS2 score compared with no IAB and a low CHADS2 score was 12.18 (95% confidence interval: 6.22-23.87, P < 0.001), after adjustment for age, sex, coronary artery disease, valvular heart disease, smoking, medications, and echocardiographic parameters. In conclusion, IAB and a high CHADS2 score independently and synergistically predict new onset AF in patients in sinus rhythm, indicating an approximately 12-fold higher risk in patients with both IAB and a high CHADS2 score. Patients meeting these criteria should have more aggressive early intervention to prevent AF.

Trophoblastic debris extruded from hydatidiform molar placentae activates endothelial cells: Possible relevance to the pathogenesis of preeclampsia.

INTRODUCTION: Preeclampsia is currently thought to be induced by a placental factor that triggers maternal endothelial activation. It is now well known that trophoblastic debris shed from the placenta into the maternal blood is associated with this disease. Hydatidiform mole is a pathological pregnancy characterised by hyperplastic trophoblast with little or no fetal development. Women with molar pregnancies may exhibit symptoms resembling preeclampsia. Deportation of trophoblastic debris occurs in molar pregnancies but, whether trophoblastic debris from molar pregnancies expresses pathogenic signals or activates endothelial cells is unknown. METHODS: Trophoblastic debris were collected from either hydatidiform molar or normal first trimester placental explants and then exposed to monolayers of endothelial cell for 24 h. Endothelial cell activation was measured by quantifying cell-surface ICAM-1using ELISA. In addition, the expressions of High mobility group box 1(HMGB1) and heat shock protein 70 (HSP70) on molar placenta were examined by immunohistochemistry and western blotting. Circulating levels of sEndoglin in molar pregnancy was also measured. RESULTS: Exposing trophoblastic debris from molar placentae increased endothelial cell surface ICAM-1 expression compared to endothelial cells exposed to trophoblastic debris from controls. Expression of HSP70 but not HMGB1 was significantly increased in hydatidiform molar placentae. The circulating levels of sEndoglin in hydatidiform molar pregnancy were not increased compared to controls. DISCUSSION: Our results suggest that trophoblastic debris from molar pregnancies induces endothelial cell activation. HSP70 but not HMGB1 expressed on hydatidiform molar placenta may be a pathogenic signal to endothelial cells.

Advanced interatrial block predicts clinical recurrence of atrial fibrillation after catheter ablation.

BACKGROUND: It has been demonstrated that advanced interatrial block (IAB) is associated with an increased risk of atrial fibrillation (AF); however, the impact of advanced IAB on recurrence of paroxysmal AF after catheter ablation is not clear. METHODS: 204 consecutive patients with paroxysmal AF who underwent index circumferential pulmonary vein (PV) isolation were prospectively enrolled. In all patients, a resting electrocardiogram in sinus rhythm was evaluated for the presence of advanced IAB, defined as a P-wave duration >120ms and biphasic (±) morphology in the inferior leads. Advanced IAB was detected in 20.1% of patients. AF recurrence was defined as the occurrence of confirmed atrial tachyarrhythmia lasting more than 30s beyond 3 months after the catheter ablation in the absence of any antiarrhythmic treatment. RESULTS: During the mean follow-up period of 13.9±6.2 months (range, 3-27 months), 62 patients (30.4%) developed recurrence of AF. The recurrence rate was higher in patients with advanced IAB than those without advanced IAB (46.3% vs. 26.4%, p=0.006). Cox regression analysis with adjustment for age, P-wave duration, CHADS2 score, and PV isolation identified advanced IAB (hazard ratio, 2.111; 95% confidence interval, 1.034-4.308; p=0.040) and left atrial diameter (hazard ratio, 1.051; 95% confidence interval, 1.004-1.100; p=0.034) as two independent predictors of recurrence of AF. CONCLUSIONS: Patients with advanced IAB were at an increased risk of AF recurrence after catheter ablation.

Effects of Renal Denervation from the Intima and the Adventitia of Renal Arteries on Renal Sympathetic Nerve Activity in Dogs: A Comparative Study.

OBJECTIVES: This study was designed to observe the efficacy and safety of renal denervation from the inside and outside of renal arteries. METHODS: Fourteen beagles were randomly divided into a control group (n = 4) and treatment group (n = 10). One renal artery in every beagle of the treatment group was randomly assigned to an intimal group (10 renal arteries) which underwent percutaneous renal denervation from the inside, and another renal artery was assigned to an adventitial group (10 renal arteries) which underwent renal denervation from the outside by laparotomy. RESULTS: Compared with the intimal group, the renal norepinephrine (NE) concentration in the adventitial group had significantly decreased (p = 0.003) at 3 months postsurgery. Renal artery HE staining showed that the perineurium from the adventitial group appeared thickened. Western blotting showed that renal tissue tyrosine hydroxylase (TH) protein expression in the adventitial group was significantly lower than that in the intimal group (p < 0.01) at 3 months postsurgery. There was a renal artery stenosis and a renal atrophy in the intimal group after 1 month of follow-up. CONCLUSION: The inhibitory effect on renal sympathetic nerve activity was more effective in the adventitial group than the intimal group, and renal denervation in the former group was safe.

Efficacy of catheter ablation for atrial fibrillation in patients with a permanent pacemaker for atrioventricular block.

Catheter ablation has been established to be an effective therapy for drug-refractory paroxysmal AF and is recommended as the treatment of choice for many patients, including those with a permanent pacemaker (PM). However, the clinical efficacy of catheter ablation of paroxysmal AF in patients with a permanent PM for atrioventricular block (AVB) is not clear. Twenty-nine patients with a permanent PM for AVB (AVB + PM group), and 145 age- and gender-matched control patients (on a 1:5 basis) without AVB and without a permanent PM (no-AVB + no-PM group), were included in this study. Atrial fibrillation (AF) recurrence was defined as the occurrence of confirmed atrial tachyarrhythmia lasting more than 30 seconds beyond 3 months after catheter ablation in the absence of any antiarrhythmic treatment. During a mean follow-up period of 14.2 ± 8.6 months (range, 3-30 months), 54 patients (31.0%) developed recurrence of AF. The recurrence rate was higher in the AVB + PM group than in the no-AVB + no-PM group (48.3% versus 27.6%, P = 0.005). Cox regression analysis with adjustment for age, valvular heart disease, AVB and a PM together, left atrial (LA) diameter and PV isolation identified LA diameter (hazard ratio 1.054, 95% confidence interval 1.001-1.110, P = 0.047) and AVB and a PM together (hazard ratio 2.095, 95% confidence interval 1.109-3.960, P = 0.023) as two independent predictors of recurrence of AF. Patients with a permanent PM for AVB were at an increased risk of recurrence of AF after catheter ablation.

Effects of thyroid dysfunction on the severity of coronary artery lesions and its prognosis.

BACKGROUND: Abnormal thyroid hormone metabolism influences the occurrence and progress of coronary heart disease (CHD). The aim of the present study was to analyze the severity of coronary artery lesions and the prognosis of thyroid dysfunction patients admitted for coronary angiography (CAG). METHODS: From July 2011 to July 2012, 605 consecutive patients with suspected coronary heart disease admitted for CAG were selected. The patients were divided into three groups, based on their thyroid function prior to CAG: euthyroid group (n=455 patients), low T3 syndrome group (n=96 patients), and hypothyroidism group (n=54 patients). All patients underwent CAG. Then the severity of coronary artery lesions was assessed by Gensini scores. All patients were followed up for major adverse cardiac events. RESULTS: The prevalence of CHD in low T3 syndrome group and hypothyroidism group was significantly higher than that in the euthyroid group (p<0.001 and p=0.004, respectively). Moreover, the severity of coronary artery lesions in low T3 syndrome group and hypothyroidism group was significantly greater than that in the euthyroid group (all p<0.001). Multinomial logistic regression analysis demonstrated that low T3 syndrome was an independent risk factor of coronary artery moderate [odds ratio (OR)=4.268, 95% CI: 3.294-7.450, p=0.016] and severe (OR=4.294, 95% CI: 2.259-9.703, p<0.001) lesions. The mean duration of follow-up was 15.3±3.8 months; patients with thyroid dysfunction had a significantly worse prognosis as compared to those in the euthyroid group for the composite end-point (p<0.01). Moreover, the incidence of the composite end-point (all-cause death, non-fatal myocardial infarction, and coronary revascularization) was significantly higher in low T3 syndrome group and hypothyroidism group compared with that of in the euthyroid group (all p<0.001). CONCLUSIONS: The patients with hypothyroidism and low T3 syndrome had a high prevalence of CHD, increased severity of coronary artery lesions and poor prognosis.