Negative feedback by IRE1β optimizes mucin production in goblet cells

In mammals, the prototypical endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has diverged into two paralogs. IRE1α is broadly expressed and mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA during ER stress. By contrast, IRE1β is expressed selectively in the digestive tract, and its function remains unclear. Here, we report that IRE1β plays a distinctive role in mucin-secreting goblet cells. In IRE1β-/- mice, aberrant mucin 2 (MUC2) accumulated in the ER of goblet cells, accompanied by ER distension and elevated ER stress signaling such as increased XBP1 mRNA splicing. In contrast, conditional IRE1α-/- mice showed no such ER distension but a marked decrease in spliced XBP1 mRNA. mRNA stability assay revealed that MUC2 mRNA was greatly stabilized in IRE1β-/- mice. These findings suggest that in goblet cells, IRE1β, but not IRE1α, promotes efficient protein folding and secretion in the ER by optimizing the level of mRNA encoding their major secretory product, MUC2

Increased Plasma Levels of 8-Hydroxydeoxyguanosine Are Associated with Development of Colorectal Tumors

Increased oxidative stress is generally thought to be associated with tumorigenesis. In this cross-sectional study, we evaluated plasma 8-hydroxydeoxyguanosine (8-OHdG) levels in patients with colorectal adenoma and cancer, as a surrogate marker of oxidative damage to deoxyribonucleic acid (DNA). We collected blood samples from 58 patients with adenoma, 32 with early cancer, 25 with advanced cancer, and 36 without polyps or cancer (as controls), and measured plasma levels of 8-OHdG by enzyme-linked immunosorbent assay. Univariate analysis by logistic regression showed that an increased level of 8-OHdG was a significant risk for adenoma [odds ratio (OR) 1.393, 95% confidence interval (CI) 1.008–1.926, p = 0.045]. In patients with early cancer, univariate analysis revealed significant differences for age, body mass index (BMI), systolic blood pressure, and 8-OHdG level. Subsequent multivariate analysis revealed that 8-OHdG [OR 1.627, 95% CI 1.079–2.453, p = 0.020] and BMI [OR 1.283, 95% CI 1.038–1.585, p = 0.021] were significant risk factors for early cancer. However, 8-OHdG was not a significant risk factor for advanced cancer. Our results suggest that an increased plasma level of 8-OHdG is associated with development of colorectal adenoma and cancer

Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response

Recognition of viral RNA structures by the intracytosolic RNA helicase RIG-I triggers induction of innate immunity. Efficient induction requires RIG-I ubiquitination by the E3 ligase TRIM25, its interaction with the mitochondria-bound MAVS protein, recruitment of TRAF3, IRF3- and NF-κB-kinases and transcription of Interferon (IFN). In addition, IRF3 alone induces some of the Interferon-Stimulated Genes (ISGs), referred to as early ISGs. Infection of hepatocytes with Hepatitis C virus (HCV) results in poor production of IFN despite recognition of the viral RNA by RIG-I but can lead to induction of early ISGs. HCV was shown to inhibit IFN production by cleaving MAVS through its NS3/4A protease and by controlling cellular translation through activation of PKR, an eIF2α-kinase containing dsRNA-binding domains (DRBD). Here, we have identified a third mode of control of IFN induction by HCV. Using HCVcc and the Huh7.25.CD81 cells, we found that HCV controls RIG-I ubiquitination through the di-ubiquitine-like protein ISG15, one of the early ISGs. A transcriptome analysis performed on Huh7.25.CD81 cells silenced or not for PKR and infected with JFH1 revealed that HCV infection leads to induction of 49 PKR-dependent genes, including ISG15 and several early ISGs. Silencing experiments revealed that this novel PKR-dependent pathway involves MAVS, TRAF3 and IRF3 but not RIG-I, and that it does not induce IFN. Use of PKR inhibitors showed that this pathway requires the DRBD but not the kinase activity of PKR. We then demonstrated that PKR interacts with HCV RNA and MAVS prior to RIG-I. In conclusion, HCV recruits PKR early in infection as a sensor to trigger induction of several IRF3-dependent genes. Among those, ISG15 acts to negatively control the RIG-I/MAVS pathway, at the level of RIG-I ubiquitination.These data give novel insights in the machinery involved in the early events of innate immune response

Temporal non-uniformity of LV wall expansion

Background: Early-diastolic left ventricular (LV) longitudinal expansion is delayed with diastolic dysfunction. We hypothesized that, in patients with heart failure (HF) regardless of LV ejection fraction (EF), there is diastolic temporal non-uniformity with a delay of longitudinal relative to circumferential expansion. Methods and Results: Echocardiography was performed in 143 HF patients: 50 with preserved EF (HFpEF) and 93 with reduced EF (HFrEF) and 31 normal controls. The delay of early-diastolic mitral annular velocity from the mitral Doppler E (TE-e′) was measured as a parameter of the longitudinal-expansion delay. The delay of the longitudinal early-diastolic global strain rate (SRE) relative to circumferential SRE (DelayC-L) was calculated as a parameter of temporal non-uniformity. Intra LV pressure difference (IVPD) was estimated by using color M-mode Doppler data as a parameter of LV diastolic suction. Although normal controls had symmetrical LV expansion in early diastole, TE-e′ and DelayC-L were significantly prolonged in HF regardless of EF (P<0.01 vs controls for all). Multivariate analysis revealed that DelayC-L was the independent determinant of IVPD among the parameters of LV geometry and contraction (β=-0.21, P<0.05). Conclusion: An abnormal temporal non-uniformity of early-diastolic expansion is present in HF regardless of EF, which was associated with reduced LV suction

Association of peripartum troponin I levels with left ventricular relaxation in women with hypertensive disorders of pregnancy

Objective Women with hypertensive disorders of pregnancy (HDP) show elevated risk of heart failure despite decreased circulating plasma volume compared with those with normotensive control pregnancies (NCP). This study was performed to better characterise the heart in women with HDP and determine whether high-sensitivity troponin I (hs-TnI) around childbirth predicts reduced left ventricular (LV) relaxation at 1 month postpartum. Methods Echocardiography was performed longitudinally during the first, second and third trimesters and immediately postpartum within 1 week and 1 month postpartum in 24 women with HDP, with simultaneous determination of blood variables in comparison with 51 women with NCP. Results Compared with NCP, HDP showed greater antepartum left atrial (LA) volume, LV mass and inferior vena cava (IVC) diameter, higher peripartum brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide and hs-TnI with the highest value immediately postpartum, and lower early diastolic mitral annular velocity (e') during pregnancy/postpartum. In analyses of data on HDP and NCP, hs-TnI at the third trimester as well as that immediately postpartum was negatively correlated with later e' at 1 month postpartum. The areas under the receiver operating characteristic curves were 0.82 and 0.81 for hs-TnI at the third trimester and immediately postpartum, respectively, in the prediction of reduced LV relaxation at 1 month postpartum. Conclusion Reduced LV diastolic function and decreased splanchnic blood reservoir may contribute to the increased third trimester IVC diameter and LA volume in women with HOP. The rise in hs-TnI around childbirth was associated with poor LV relaxation ability at 1 month postpartum

Relations of Strain Parameters to Wall Stress

Whether and how left ventricular (LV) strain and strain rate correlate with wall stress is not known. Furthermore, it is not determined whether strain or strain rate is less dependent on the afterload. In 41 healthy young adults, LV global peak strain and systolic peak strain rate in the longitudinal direction (LS and LSR, respectively) and circumferential direction (CS and CSR, respectively) were measured layer-specifically using speckle tracking echocardiography (STE) before and during a handgrip exercise. Among all the points before and during the exercise, all the STE parameters significantly correlated linearly with wall stress (LS: r = -0.53, p < 0.01, LSR: r = -0.28, p < 0.05, CS in the inner layer: r = -0.72, p < 0.01, CSR in the inner layer: r = -0.47, p < 0.01). Strain more strongly correlated with wall stress than strain rate (r = -0.53 for LS vs. r = -0.28 for LSR, p < 0.05; r = -0.72 for CS vs. r = -0.47 for CSR in the inner layer, p < 0.05), whereas the interobserver variability was similar between strain and strain rate (longitudinal 6.2 vs. 5.2 %, inner circumferential 4.8 vs. 4.7 %, mid-circumferential 7.9 vs. 6.9 %, outer circumferential 10.4 vs. 9.7 %), indicating that the differences in correlation coefficients reflect those in afterload dependency. It was thus concluded that LV strain and strain rate linearly and inversely correlated with wall stress in the longitudinal and circumferential directions, and strain more strongly depended on afterload than did strain rate. Myocardial shortening should be evaluated based on the relationships between these parameters and wall stress

A new method to estimate pulmonary vascular resistance using diastolic pulmonary artery-right ventricular pressure gradients derived from continuous-wave Doppler velocity measurements of pulmonary regurgitation

Pulmonary vascular resistance (PVR) is an important hemodynamic parameter in patients with heart failure, especially when the pulmonary arterial pressure is lower due to reduced stroke volume. Several echocardiographic methods to estimate PVR have been proposed, but their applications in patients with organic left-sided heart diseases have been limited. The aim of the present study was to examine the usefulness of our new method to estimate PVR (PVRPR) based on the continuous-wave Doppler velocity measurements of pulmonary regurgitation in these patients. In 43 patients who underwent right heart catheterization, PVRPR was calculated as the difference between the Doppler-derived early- and end-diastolic pulmonary artery (PA)-right ventricular (RV) pressure gradients divided by the cardiac output measured in the left ventricular outflow tract by echocardiography. The PVRPR correlated well with invasive PVR (PVRCATH) (r = 0.81, p 3 Wood units, WU), the area under the curve was the greatest for PVRPR (0.964) compared to the conventional PVRs (0.649-0.839). PVRPR had 83 % sensitivity and 100 % specificity at the optimal cut-off value of 3.10 WU in identifying patients with PVRCATH > 3 WU. Our simple and theoretical PVRPR is useful for the noninvasive estimation of PVR

Characteristic systolic waveform of left ventricular longitudinal strain rate in patients with hypertrophic cardiomyopathy

We analyzed the waveform of systolic strain and strain-rate curves to find a characteristic left ventricular (LV) myocardial contraction pattern in patients with hypertrophic cardiomyopathy (HCM), and evaluated the utility of these parameters for the differentiation of HCM and LV hypertrophy secondary to hypertension (HT). From global strain and strain-rate curves in the longitudinal and circumferential directions, the time from mitral valve closure to the peak strains (T-LS and T-CS, respectively) and the peak systolic strain rates (T-LSSR and T-CSSR, respectively) were measured in 34 patients with HCM, 30 patients with HT, and 25 control subjects. The systolic strain-rate waveform was classified into 3 patterns ("V", "W", and "√" pattern). In the HCM group, T-LS was prolonged, but T-LSSR was shortened; consequently, T-LSSR/T-LS ratio was distinctly lower than in the HT and control groups. The "√" pattern of longitudinal strain-rate waveform was more frequently seen in the HCM group (74 %) than in the control (4 %) and HT (20 %) groups. Similar but less distinct results were obtained in the circumferential direction. To differentiate HCM from HT, the sensitivity and specificity of the T-LSSR/T-LS ratio <0.34 and the "√"-shaped longitudinal strain-rate waveform were 85 and 63 %, and 74 and 80 %, respectively. In conclusion, in patients with HCM, a reduced T-LSSR/T-LS ratio and a characteristic "√"-shaped waveform of LV systolic strain rate was seen, especially in the longitudinal direction. The timing and waveform analyses of systolic strain rate may be useful to distinguish between HCM and HT