MANF ameliorates DSS-induced mouse colitis via restricting Ly6ChiCX3CR1int macrophage transformation and suppressing CHOP-BATF2 signaling pathway.

Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible secreting protein, has evolutionarily conserved immune-regulatory function that contributes to the negative regulation of inflammation in macrophages. In this study, we investigated the profiles of MANF in the macrophages of the patients with active inflammatory bowel disease (IBD) and the mice with experimental colitis, which was induced in both myeloid cell-specific MANF knockout mice and wild-type mice by 3% dextran sodium sulfate (DSS) for 7 days. We found that MANF expression was significantly increased in intestinal macrophages from both the mice with experimental colitis and patients with active IBD. DSS-induced colitis was exacerbated in myeloid cell-specific MANF knockout mice. Injection of recombinant human MANF (rhMANF, 10 mg·kg-1·d-1, i.v.) from D4 to D6 significantly ameliorated experimental colitis in DSS-treated mice. More importantly, MANF deficiency in myeloid cells resulted in a dramatic increase in the number of Ly6ChiCX3CRint proinflammatory macrophages in colon lamina propria of DSS-treated mice, and the proinflammatory cytokines and chemokines were upregulated as well. Meanwhile, we demonstrated that MANF attenuated Th17-mediated immunopathology by inhibiting BATF2-mediated innate immune response and downregulating CXCL9, CXCL10, CXCL11 and IL-12p40; MANF functioned as a negative regulator in inflammatory macrophages via inhibiting CHOP-BATF2 signaling pathway, thereby protecting against DSS-induced mouse colitis. These results suggest that MANF ameliorates colon injury by negatively regulating inflammatory macrophage transformation, which shed light on a potential therapeutic target for IBD.

Elevated soluble ST2 and depression increased the risk of all-cause mortality and hospitalization in patients with heart failure.

This study aimed to assess the predictive effect of soluble ST2 (sST2) and depressive symptoms in patients with heart failure (HF) and to determine whether the prognosis of HF patients with preserved ejection fraction (HFpEF) differs from those with reduced ejection fraction (HFrEF). A cohort of 233 HF patients was followed for 1 year. Depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale. The primary endpoint was all-cause mortality and HF-related hospitalization. For the analysis of survival, the left ventricular ejection fraction (LVEF) cut-offs for defining HFpEF were set at 50%, 45%, and 40%, respectively. With increasing LVEF, levels of sST2 were gradually decreased (45.2 ng/mL, 35.8 ng/mL, and 32.1 ng/mL in patients with LVEF ≤ 40%, 41% to 49%, and ≥ 50%, respectively, P for trend < 0.001), as well as the prevalence of depressive symptoms (35.4%, 33.3%, and 20.4%, respectively, P for trend = 0.022). After 1-year follow-up, 128 patients (54.9%) achieved the primary endpoint and 47 patients (20.2%) died. Depressive symptoms were independent risk factors of all-cause mortality and HF-related hospitalization. The combined presence of elevated sST2 (> 36.0 ng/mL) and depressive symptoms was associated with a 4.9-fold increased risk of the primary endpoint. Regardless of LVEF cut-offs, the associated risk of adverse outcomes in HFpEF was as high as in HFrEF after adjustment for significant risk factors including sST2 and N-terminal pro-brain natriuretic peptide. In conclusion, depressive symptoms provided additional prognostic information to that of sST2 in HF patients. The prognosis of HFpEF patients was similar to that of HFrEF patients.

Relaxin-2 improves diastolic function of pressure-overloaded rats via phospholamban by activating Akt.

BACKGROUND: Relaxin is a peptide hormone which has been demonstrated to be safe and has a therapeutic effect on acute heart failure in clinic trials. However, its effect on diastolic function is still unknown. The aims of the study were to determine whether relaxin could improve the diastolic function in pressure-overloaded rat model and to analyze potential mechanisms. METHODS AND RESULTS: In the present study, a pressure-overloaded rat model induced by transaortic constriction (TAC) was established. Four weeks after TAC, echocardiography was performed and then all the rat models were randomly divided into 3 groups: models without intramyocardial injection (TAC), with intramyocardial injection of empty adenoviral vector (TAC+GFP) and adenoviral vector overexpression relaxin-2 gene (TAC+RLN2). A sham group was also included. Twelve days after intramyocardial injection, echocardiography and hemodynamics were carried out to evaluate diastolic function in sham, TAC, TAC+GFP and TAC+RLN2 groups. Then hearts were harvested for subsequent examinations. The results indicated that relaxin-2 had ameliorated diastolic function in the pressure-overloaded rats. Compared with the TAC and TAC+GFP groups, the relaxin-2 gene transfer increased phosphorylation of Akt at both the Ser473 and Thr308 sites. Meanwhile, it increased the Ser16 and Thr17- phosphorylation levels of phospholamban (PLB). Furthermore, SERCA2 activity was enhanced in the TAC+RLN2 group more than in the TAC and TAC+GFP groups. CONCLUSIONS: These results demonstrated that relaxin-2 gene therapy improved diastolic function in pressure-overloaded rats. The potential mechanism may be that relaxin-2 gene transfer enhances SERCA2 activity in hearts by increasing phospholamban phosphorylation through nuclear-targeted Akt phosphorylation.