Background: Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). Methods: Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. Results: The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. Conclusion: Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.

We aimed to clarify the effect of the hemoglobin glycation index (HGI)–diabetes mellitus (DM) system in evaluating the risk of incident stroke. We followed up on 2934 subjects in rural regions of Northeast China, established Cox proportional hazards models to evaluate the effects of the HGI–DM system in describing stroke risk, and further conducted a discrimination analysis to confirm the improvement in HGI based on the traditional stroke risk model. After a median of 4.23 years of follow-up, 79 subjects developed stroke or related death. DM-high HGI condition significantly elevated the risk of incident stroke (hazard ratio (HR): 2.655, 95% confidence interval (CI): 1.251–5.636). In addition, higher HGI levels elevated the risk of stroke, even if the patients did not have DM (HR: 1.701, 95% CI: 1.136–2.792), but DM failed to bring an extra risk of incident stroke to patients with lower HGI levels (HR: 1.138, 95% CI: 0.337–3.847). The discrimination analysis indicated that the integrated discrimination index (IDI) of the HGI model was 0.012 (95% CI: 0.007–0.015) and that the net reclassification index (NRI) was 0.036 (95% CI: 0.0198–0.0522). These results indicated HGI was associated with the onset of stroke, and high HGI indicated an aggravated trend in glycemic status and increased risk of incident stroke. The HGI–DM system enabled us to identify the different glucose statuses of patients, to conduct suitable treatment strategies, as well as to improve the predictability of incident stroke based on the traditional model.

Summary Based on the use of Osteoporosis Self-Assessment Tool for Asians (OSTA) to assess osteoporosis risk, we found that short sleep duration and taking a daytime nap had an increased risk of osteoporosis. Purpose To explore the associations between different sleep patterns with osteoporosis. Methods 3659 postmenopausal women (average age of 60 years) were divided into low, middle, and high osteoporosis risk categories based on the Osteoporosis Self-Assessment Tool for Asians (OSTA). After having collected by a standard questionnaire, total and nocturnal sleep duration was collapsed to form categories of ≤ 6 h, > 6 h and ≤ 7 h, > 7 h and ≤ 8 h, > 8 h and ≤ 9 h, > 9 h, and daytime nap duration of 0 h and > 0 h. Results As a categorical variable, the total sleep duration of ≤ 6 h per day (OR = 1.34, 95% CI 1.04–1.72), nocturnal sleep duration of ≤ 6 h per night (OR = 1.65, 95% CI 1.24–2.18), and taking a daytime nap (OR = 1.33, 95% CI 1.09–1.64) had higher osteoporosis risk after adjustment for covariates. As a continuous variable, after the adjustment for covariates, both longer total (OR = 0.86, 95% CI 0.78–0.94) and nocturnal sleep duration (OR = 0.83, 95% CI 0.76–0.91) had lower risk of osteoporosis risk while taking longer daytime nap (OR = 1.10, 95% CI 1.02–1.19) had higher osteoporosis risk. Conclusions Postmenopausal women with both short total and nocturnal sleep duration (6 h or less) and taking a daytime nap had increased osteoporosis risk as assessed by OSTA.

Purpose: To explore the predictive value of ACEF scores for identifying the risk of cardiovascular disease (CVD) in the general population. Methods: A total of 8613 participants without a history of CVD were enrolled in the follow-up. The endpoint was CVD incidence, defined as stroke or coronary heart disease (CHD) diagnosed during the follow-up period. Cox regression analyses were used to calculate hazard ratios (HRs) with respect to the age, creatinine, and ejection fraction (ACEF) scores and CVD. A Kaplan–Meier curve was used to analyze the probability of CVD in different quartiles of ACEF. Restricted cubic spline was used to further explore whether the relationship between ACEF and CVD was linear. Finally, we assessed the discriminatory ability of ACEF for CVD using C-statistics, net reclassification index, and integrated discrimination improvement (IDI). Results: During a median follow-up period of 4.66 years, 388 participants were diagnosed with CVD. The Kaplan–Meier curve showed that ACEF was associated with CVD, and participants with high ACEF scores were significantly more likely to be diagnosed with CVD compared to participants with low ACEF scores in the general population. In the multivariate Cox regression analysis, the adjusted HRs for four quartiles of ACEF were as follows: the first quartile was used as a reference; the second quartile: HR = 2.33; the third quartile: HR = 4.81; the fourth quartile: HR = 8.00. Moreover, after adding ACEF to the original risk prediction model, we observed that new models had higher C-statistic values of CVD than the traditional model. Furthermore, the results of both NRI and IDI were positive, indicating that ACEF enhanced the prediction of CVD. Conclusions: Our study showed that the ACEF score was associated with CVD in the general population in northeastern China. Furthermore, ACEF could be a new tool for identifying patients at high risk of primary CVD in the general population.