Melatonin Attenuates Vascular Smooth Muscle Contraction Through the γ-Secretase/Notch Intracellular Domain/Myocardin Pathway.

ABSTRACT: Inositol 1, 4, 5-trisphosphate (IP3) signaling-mediated calcium release drives the contraction of vascular smooth muscles and hence regulates blood vessel volume and blood pressure. Melatonin supplementation has been suggested to be beneficial for hypertension. To determine whether the blood pressure-lowering effect of melatonin was accounted for by IP3 signaling, we evaluated the vasoconstriction response and IP3 signaling in isolated mouse thoracic aortic rings during melatonin incubation. C57BL/6 mice were given intraperitoneal injections daily with melatonin, and the systolic blood pressure and contractility of aortic rings from melatonin-treated mice were decreased, and the contraction suppression effect of melatonin was attributed to the impaired expression of contractile proteins in vascular smooth muscle cells rather than IP3 signaling. Our results further showed that melatonin increased the expression of γ-secretase, which could cleave and release the notch intracellular domain, and the notch intracellular domain prevented the transcription of contractile genes by interfering with the interaction between serum response factor and myocardin, the master regulator of contractile protein. In this article, we report a novel mechanism by which melatonin regulates smooth muscle contractility that does not depend on IP3 signaling.

Pittsburgh Sleep Quality Index score predicts all-cause mortality in Chinese dialysis patients.

BACKGROUND: The relationship between Pittsburgh Sleep Quality Index (PSQI) score and survival of dialysis patients has not been well studied. The aim of this study was to explore the association between PSQI score and all-cause mortality in dialysis patients. METHODS: Fifty-one hemodialysis and 58 peritoneal dialysis patients were enrolled in this study. PSQI score > 5 and ≤ 5 indicated "poor sleepers" and "good sleepers", respectively. The primary outcome was all-cause mortality. Kaplan-Meier survival curve and Cox proportional hazards regression analysis were performed. RESULTS: The median PSQI score was 7.0 (4.0-10.0). Sixty-seven (61.5%) patients had poor sleep quality (SQ). Compared with good sleepers, poor sleepers had significantly lower levels of hemoglobin [74.0 (61.0, 85.0) vs. 78.0 (68.0, 97.0), P = 0.03] and serum bicarbonate (18.0 ± 4.5 vs. 20.0 ± 3.7, P = 0.022). The follow-up time was 69.1 ± 29.9 months. By multivariate Cox proportional hazards analysis, PSQI total score was the independent risk factor of all-cause mortality [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.05-1.36, P = 0.007]. Restricted cubic spline (RCS) analysis showed that 7 was the cutoff value at which the effect of PSQI score on mortality changed. Patients with a PSQI score > 7 had a 2.96-fold increased risk of all-cause mortality (HR 2.96, 95% CI 1.15-7.61, P = 0.025). CONCLUSIONS: PSQI score can be used as a predictor of all-cause mortality in dialysis patients, and those with PSQI > 7 were associated with increased odds of mortality.

Pyroptotic cell-derived microparticle: An atherogenic factor in infectious diseases.

Chronic infection is considered a risk factor for atherosclerosis. The link between infectious agents and atherosclerosis is manifested by the presence of infection-induced pyroptotic cells in atherosclerotic lesions. Pyroptosis is an inflammatory form of programmed cell death that occurs most frequently upon infection. However, inflammation is not the only cause by which pyroptosis involved in atherosclerosis. During pyroptosis, a large amount of microparticles are released from pyroptotic cells, which not only transfer inflammatory mediators to arterial vessel, but also mediate the interaction between a variety of cells, leading to endothelial injury, macrophage infiltration, vascular smooth muscle cell migration and proliferation, thereby accelerating atherosclerosis. Thus, we proposed hypothesis that pyroptotic cell-derived microparticle is an atherogenic factor in infectious diseases.

Systemic inflammation modulates the ability of serum ferritin to predict all-cause and cardiovascular mortality in peritoneal dialysis patients.

BACKGROUND: This study aimed to ascertain whether the correlation of high serum ferritin with mortality is affected by systemic inflammation and to investigate the optimal serum ferritin level for predicting death when inflammation is considered in peritoneal dialysis (PD) patients. METHODS: We classified 221 patients into four groups according to serum ferritin concentration (100 µg/L) and high-sensitivity CRP (hs-CRP) level (3 mg/L), and followed them regularly from the date of catheterization to Dec 31, 2016, at Sun Yat-Sen Memorial Hospital, China. Clinical and biochemical data were collected at baseline, and clinical outcomes such as all-cause and cardiovascular mortality were assessed. RESULTS: During a median follow-up of 35 months (3 ~ 109 months), 50 (22.6%) deaths occurred. Cardiovascular disease (46.0%) was the most common cause of death, followed by infection (10.0%). The Kaplan-Meier survival analysis and log-rank test revealed significantly worse survival accumulation among PD patients with higher serum ferritin (≥100 µg/L) under elevated hsCRP levels (> 3 mg/L) (P = 0.022). A multivariate Cox regression analysis revealed that an increased serum ferritin level was independently associated with a higher risk of all-cause and cardiovascular mortality in PD patients (HR = 3.114, P = 0.021; and HR = 9.382, P = 0.032) with hsCRP above 3 mg/L after adjusting for relevant confounding factors. CONCLUSION: Higher serum ferritin levels were associated with an increased risk of all-cause and cardiovascular mortality in patients undergoing PD only in the presence of elevated hsCRP levels. The correlation of serum ferritin with poor outcome should take into consideration systemic inflammation.