Zbtb16 increases susceptibility of atrial fibrillation in type 2 diabetic mice via Txnip-Trx2 signaling.

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, and recent epidemiological studies suggested type 2 diabetes mellitus (T2DM) is an independent risk factor for the development of AF. Zinc finger and BTB (broad-complex, tram-track and bric-a-brac) domain containing 16 (Zbtb16) serve as transcriptional factors to regulate many biological processes. However, the potential effects of Zbtb16 in AF under T2DM condition remain unclear. Here, we reported that db/db mice displayed higher AF vulnerability and Zbtb16 was identified as the most significantly enriched gene by RNA sequencing (RNA-seq) analysis in atrium. In addition, thioredoxin interacting protein (Txnip) was distinguished as the key downstream gene of Zbtb16 by Cleavage Under Targets and Tagmentation (CUT&Tag) assay. Mechanistically, increased Txnip combined with thioredoxin 2 (Trx2) in mitochondrion induced excess reactive oxygen species (ROS) release, calcium/calmodulin-dependent protein kinase II (CaMKII) overactivation, and spontaneous Ca2+ waves (SCWs) occurrence, which could be inhibited through atrial-specific knockdown (KD) of Zbtb16 or Txnip by adeno-associated virus 9 (AAV9) or Mito-TEMPO treatment. High glucose (HG)-treated HL-1 cells were used to mimic the setting of diabetic in vitro. Zbtb16-Txnip-Trx2 signaling-induced excess ROS release and CaMKII activation were also verified in HL-1 cells under HG condition. Furthermore, atrial-specific Zbtb16 or Txnip-KD reduced incidence and duration of AF in db/db mice. Altogether, we demonstrated that interrupting Zbtb16-Txnip-Trx2 signaling in atrium could decrease AF susceptibility via reducing ROS release and CaMKII activation in the setting of T2DM.

Ntsr1 contributes to pulmonary hypertension by enhancing endoplasmic reticulum stress via JAK2-STAT3-Thbs1 signaling.

Pulmonary hypertension (PH) is a severe clinical syndrome with pulmonary vascular remodeling and poor long-term prognosis. Neurotensin receptor 1 (Ntsr1), serve as one of the G protein-coupled receptors (GPCRs), implicates in various biological processes, but the potential effects of Ntsr1 in PH development are unclear. The Sugen/Hypoxia (SuHx) or monocrotaline (MCT) induced rat PH model was used in our study and the PH rats showed aggravated pulmonary artery remodeling and increased right ventricular systolic pressure (RVSP). Our results revealed that Ntsr1 induced endoplasmic reticulum (ER) stress response via ATF6 activation contributed to the development of PH. Moreover, RNA-sequencing (RNA-seq) and phosphoproteomics were performed and the Ntsr1-JAK2-STAT3-thrombospondin 1 (Thbs1)-ATF6 signaling was distinguished as the key pathway. In vitro, pulmonary artery smooth muscle cells (PASMCs) under hypoxia condition showed enhanced proliferation and migration properties, which could be inhibited by Ntsr1 knockdown, JAK2 inhibitor (Fedratinib) treatment, STAT3 inhibitior (Stattic) treatment, Thbs1 knockdown or ATF6 knockdown. In addition, adeno-associated virus 1 (AAV1) were used to knockdown the expression of Ntsr1, Thbs1 or ATF6 in rats and reversed the phenotype of PH. In summary, our results reveal that Ntsr1-JAK2-STAT3-Thbs1 pathway can induce enhanced ER stress via ATF6 activation and increased PASMC proliferation and migration capacities, which can be mechanism of the pulmonary artery remodeling and PH. Targeting Ntsr1 might be a novel therapeutic strategy to ameliorate PH.

Macrophages facilitate post myocardial infarction arrhythmias: roles of gap junction and KCa3.1.

Effective therapeutic targets against post-myocardial infarction (MI) arrhythmias remain to be discovered. We aimed to investigate the role of macrophages in post-MI arrhythmias. Methods: Mononuclear cell accumulation, macrophage polarization from M0 to M1 subset, and gap junction formation were analyzed in MI patients and MI mice by flow cytometry, immunofluorescence and patch clamping. Differentially expressed genes were identified by RNA sequencing. Macrophages and cardiomyocytes were cocultured in vitro, and the effects of gap junction and KCa3.1 on electrophysiological properties were assessed by patch clamping. The effects of KCa3.1 inhibition on post-MI arrhythmias were assessed by intracardiac stimulation and ambulatory electrocardiograms in vivo. Results: Percentage of pro-inflammatory mononuclear cells were significantly elevated in patients with post-MI arrhythmias compared with MI patients without arrhythmias and healthy controls (p<0.001). Macrophages formed gap junction with cardiomyocytes in MI border zones of MI patient and mice, and pro-inflammatory macrophages were significantly increased 3 days post-MI (p<0.001). RNA sequencing identified Kcnn4 as the most differentially expressed gene encoding ion channel, and the upregulation is mainly attributed to macrophage accumulation and polarization into pro-inflammatory subset. In vitro coculture experiments demonstrated that connection with M0 macrophages via gap junction slightly shortened the action potential durations (APDs) of cardiomyocytes. However, the APD90 of cardiomyocytes connected with M1 macrophages were significantly prolonged (p<0.001), which were effectively attenuated by gap junction inhibition (p=0.002), KCa3.1 inhibition (p=0.008), KCa3.1 silencing (p<0.001) and store-operated Ca2+ channel inhibition (p=0.005). In vivo results demonstrated that KCa3.1 inhibition significantly decreased the QTc durations (p=0.031), intracardiac stimulation-induced ventricular arrhythmia durations (p=0.050) and incidence of premature ventricular contractions (p=0.030) in MI mice. Conclusion: Macrophage polarization leads to APD heterogeneity and post-MI arrhythmias via gap junction and KCa3.1 activation. The results provide evidences of a novel mechanism of post-MI heterogeneous repolarization and arrhythmias, rendering macrophages and KCa3.1 to be potential therapeutic targets.

Curcumin protects cardiac myocyte against hypoxia-induced apoptosis through upregulating miR-7a/b expression.

OBJECTIVE: Curcumin has properties of anti-inflammation, anti-oxidation, anti-infection and anti-tumor, benefiting for the treatment of many diseases. The present study was aimed to investigate the role of curcumin in myocardial infarction (MI) and its potential mechanism involving transcription factor specific protein 1 (SP1). METHODS: After receiving curcumin, C57BL/6 mice subjected to left anterior descending (LAD) coronary artery occlusion to induce MI model. Infarct size was measured by triphenyl tetrazolium chloride staining. In vitro experiments, mouse cardiac myocytes (MCM) subjected to hypoxia after the incubation of curcumin, miR-7a/b and SP1 expression levels were detected by real-time PCR and western blot. Caspase-3 activity and TUNEL assay were performed to assess the cell apoptosis. RESULTS: In animal experiments, curcumin significantly reduced the infarct size compared with the control. It also up-regulated miR-7a/b expression and down-regulated SP1 expression. In hypoxia-induced MCM, curcumin led to the decrease of cell apoptosis. Transfected MCM with miR-7a/b inhibitor, curcumin induced the decrease of cell apoptosis and SP1 expression was reversed. Transfected with pcDNA-SP1, the decrease of cardiac myocytes apoptosis after the treatment of curcumin was also reversed. CONCLUSION: Curcumin pre-treatment protected against hypoxia-induced cardiac myocytes apoptosis through the up-regulation of miR-7a/b and the down-regulation of SP1 expression.

Clinical Outcomes of Revascularization Strategies for Patients With MVD/LMCA Disease: A Systematic Review and Network Meta-Analysis.

Hybrid coronary revascularization (HCR), a new minimally invasive procedure for patients requiring revascularization for multivessel coronary lesions, combines coronary artery bypass grafting (CABG) for left anterior descending (LAD) lesions and percutaneous coronary intervention (PCI) for non-LAD coronary lesions. However, available data related to outcomes comparing the 3 revascularization therapies is limited to small studies.We conducted a search in MEDLINE, EMBASE, and the Cochrane Library of Controlled Trials up to December 31, 2014, without language restriction. A total of 16 randomized trials (n=4858 patients) comparing HCR versus PCI or off-pump CABG (OPCAB) were included in this meta-analysis. The primary outcomes were major adverse cardiac and cerebrovascular events (MACCE), all-cause death, myocardial infarction (MI), cerebrovascular events (CVE), and target vessel revascularization (TVR). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effect and fixed-effect models. Ranking probabilities were used to calculate a summary numerical value: the surface under the cumulative ranking (SUCRA) curve.No significant differences were seen between the HCR and PCI in short term (in hospital and 30 days) with regard to MACCE (odds ratio [OR] = 0.51, 95% confidence interval [CI] 0.00-2.35), all-cause death (OR = 2.09, 95% CI 0.34-7.66), MI (OR = 1.02, 95% CI 0.19-2.95), CVE (OR = 4.45, 95% CI 0.39-19.16), and TVR (OR = 6.99, 95% CI 0.17-39.39). However, OPCAB had lower MACCE than HCR (OR = 0.19, 95% CI 0.00-0.95). In midterm (1 year and 3 year), in comparison with HCR, PCI had higher all-cause death (OR = 5.66, 95% CI 0.00-13.88) and CVE (OR = 4.40, 95% CI 0.01-5.68), and lower MI (OR = 0.51, 95% CI 0.00-2.86), TVR (OR = 0.53, 95% CI 0.05-2.26), and thus the MACCE (OR = 0.51, 95% CI 0.00-2.35). Off-pump CABG presented a better outcome than HCR with significant lower MACCE (OR = 0.17, 95% CI 0.01-0.68). Surface under the cumulative ranking probabilities showed that HCR may be the superior strategy for MVD and LMCA disease when regarded to MACCE (SUCRA = 0.84), MI (SUCRA = 0.76) in short term, and regarded to MACCE (SUCRA = 0.99), MI (SUCRA = 0.94), and CVE (SUCRA = 0.92) in midterm.Hybrid coronary revascularization seemed to be a feasible and acceptable option for treatment of LMCA disease and MVD. More powerful evidences are required to precisely evaluate risks and benefits of the 3 therapies for patients who have different clinical characteristics.

In-hospital clinical outcomes of elderly patients (≥60 years) undergoing primary percutaneous coronary intervention.

Elderly patients are at high risk of mortality when they present with ST-elevation myocardial infarction (STEMI). However, the clinical outcomes of this sub-group undergoing primary percutaneous coronary intervention (PPCI) have not been well established, despite recent advances in both devices and techniques. In the present retrospective cohort study from a Chinese single center, we assessed the clinical outcomes and predictors of mortality in elderly patients (≥60 years) underwent with PPCI. The primary endpoints were immediate angiographic success and in-hospital procedural success. The secondary endpoints were all-cause death in hospital. Between January 2011 and December 2013, a total of 184 consecutive patients with acute STEMI underwent PPCI were enrolled. 116 (63.04%) patients were in the elderly group. Despite the difference in lesion complexity between groups, the immediate angiographic success rate was similar (93.97% in the elderly group, and 94.12% in the non-elderly group, P=0.966). The procedural success rate were not significantly different between the two groups (90.52% in the elderly group, and 94.12% in the non-elderly group, P=0.389). However, in-hospital mortality was statistically higher in elderly group than in the non-elderly group (8.62% Vs 1.47%, P=0.048). The major causes of death were cardiac shock and malignant arrhythmias (ventricular tachycardia and fibrillation). Our results indicate that PPCI in the elderly is feasible and has a high likelihood of immediate angiographic and procedural success.

Clinical characteristics of acute pancreatitis patients with elevated serum triglyceride concentration.

OBJECTIVE: To evaluate the clinical characteristics of acute pancreatitis (AP) patients with elevated serum triglyceride (TG) concentration. METHODS: Ninety-nine cases of AP admitted from January 2000 to January 2002 were analyzed: 28 cases comprised the TG-elevated group (serum TG >1.7 mmol/L) and 71 cases were the TG-normal group (serum TG