Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice.

BACKGROUND: Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown. METHODS: APOE (apolipoprotein E) or LDLR (low-density lipoprotein receptor) null mice treated with SHP099 were fed a Western diet for 8 weeks, while Shp2MKO:ApoE-/- or Shp2MKO:Ldlr-/- mice and exo-AAV8-SHP2E76K/ApoE-/- mice were fed a Western diet for 12 weeks. In vitro, levels of proinflammatory factors and phagocytic function were then studied in mouse peritoneal macrophages. RNA sequencing was used to identify PPARγ (peroxisome proliferative activated receptor γ) as the key downstream molecule. A PPARγ agonist was used to rescue the phenotypes observed in SHP2-deleted mice. RESULTS: Pharmacological inhibition and selective deletion in macrophages of SHP2 aggravated atherosclerosis in APOE and LDLR null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and LDLR null macrophages enhanced proinflammatory polarization and its efferocytosis was dramatically impaired. Conversely, the expression of gain-of-function mutation of SHP2 in mouse macrophages reduced atherosclerosis. The SHP2 agonist lovastatin repressesed macrophage inflammatory activation and enhanced efferocytosis. Mechanistically, RNA sequencing analysis identified PPARγ as a key downstream transcription factor. PPARγ was decreased in macrophages upon SHP2 deletion and inhibition. Importantly, PPARγ agonist decreased atherosclerosis in SHP2 knockout mice, restored efferocytotic defects, and reduced inflammatory activation in SHP2 deleted macrophages. PPARγ was decreased by the ubiquitin-mediated degradation upon SHP2 inhibition or deletion. Finally, we found that SHP2 was downregulated in atherosclerotic vessels. CONCLUSIONS: Overall, SHP2 in macrophages was found to act as an antiatherosclerotic regulator by stabilizing PPARγ in APOE/LDLR null mice.

Predictive value of extubation failure by decrease in central venous oxygen saturation: A systematic review and meta-analysis.

Background: The predictive power of extubation failure diagnosed by decrease in central venous oxygen saturation (ΔScvO2) varies by studies. Here we summarized the diagnostic value of extubation failure tested by ΔScvO2. Methods: A comprehensive online search was performed to select potentially eligible studies that evaluated the predictive power of extubation failure tested by ΔScvO2. A manual search was also performed to identify additional studies. Data were extracted to calculate the pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) to evaluate the predictive power of extubation failure. Results: Overall, five studies including 353 patients were included in this review, of whom 105 (30%) were extubation failure. The cutoff values of ΔScvO2 varied across studies, ranging from 3.8% to 5.4%. Heterogeneity between studies was assessed with an overall Q = 0.007, I2 = 0%, and P = 0.498. The pooled sensitivity and specificity for the overall population were 0.83 (95% CI: 0.74-0.90) and 0.88 (95% CI: 0.83-0.92), respectively. The pooled positive LR and negative LR were 7.2 (95%CI: 4.6-11.2) and 0.19 (95%CI: 0.12-0.31), respectively. The DOR was 38 (95% CI: 17-86). Overall, the pooled AUROC was 0.92 (95% CI: 0.90-0.94). Conclusions: The ΔScvO2 performed well in predicting extubation failure in adult mechanical ventilation patients. Further studies with a larger data set and well-designed models are required to confirm the diagnostic accuracy and utility of ScvO2 in predicting extubation outcomes in mechanical ventilation patients.

Bayesian network meta-analysis comparing hot balloon, laser balloon and cryoballoon ablation as initial therapies for atrial fibrillation.

Background: Balloon-based catheter ablation (CA) technologies, including hot balloon ablation (HBA), laser balloon ablation (LBA) and cryoballoon ablation (CBA) have been introduced in recent years as alternatives to conventional radiofrequency ablation therapy for atrial fibrillation (AF). However, the results remain controversial concerning the optimal approach. Thus, we conducted a network meta-analysis (NMA) to comprehensively evaluate the efficacy and safety of HBA, LBA and CBA. Methods: Clinical trials comparing the efficacy and safety of HBA, LBA and CBA were identified through a systematic search up to October 2022. The primary outcomes of interest were the recurrence of AF and procedure-related complications. Results: Twenty clinical trials with a total of 1,995 patients were included in the meta-analysis. The NMA results demonstrated that HBA, LBA and CBA had comparable AF recurrence rates (HBA vs. CBA: odds ratio OR = 0.88, 95% credible interval CrI: 0.56-1.4; LBA vs. CBA: OR = 1.1, 95% CrI: 0.75-1.5; LBA vs. HBA: OR = 1.2, 95% CrI: 0.70-2.0) and procedure-related complications (HBA vs. CBA: OR = 0.93, 95% CrI: 0.46-2.3; LBA vs. CBA: OR = 1.1, 95% CrI: 0.63-2.1; LBA vs. HBA: OR = 1.2, 95% CrI: 0.44-2.8). The surface under the cumulative ranking curve (SUCRA) suggested that HBA may be the optimal approach concerning the primary outcomes (SUCRA = 74.4%; 61.1%, respectively). However, HBA (40.1%) had a significantly higher incidence of touch-up ablation (TUA) than LBA (8.5%, OR = 2.8, 95% CrI: 1.1-7.1) and CBA (11.9%, OR = 3.7, 95% CrI: 1.9-7.5). LBA required more procedure time than CBA [mean difference (MD = 32.0 min, 95% CrI: 19.0-45.0 min)] and HBA (MD = 26.0 min, 95% CrI: 5.6-45.0 min), but less fluoroscopy time than HBA (MD = -9.4 min, 95% CrI: -17.0--2.4 min). Conclusions: HBA, LBA and CBA had comparable efficacy and safety as initial treatments for AF. HBA ranked highest in the primary outcomes, but at the cost of a higher incidence of TUA and longer fluoroscopy time. Systematic Review Registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022381954, identifier: CRD42022381954.

A bibliometric analysis of efferocytosis in cardiovascular diseases from 2001 to 2022.

INTRODUCTION: In recent years, efferocytosis in cardiovascular diseases has become an intense area of research. However, only a few bibliometric analyses have been conducted in this area. In this review, we used CiteSpace 5.7. R2 and VOSviewer 1.6.17 software to perform text mining and knowledge map analysis. This study summarizes the latest progress, development paths, frontier research hotspots, and future research trends in this field. MATERIALS AND METHODS: Studies on efferocytosis in cardiovascular diseases were downloaded from the Web of Science Core Collection. RESULTS: In total, 327 studies published by 506 institutions across 42 countries and regions were identified. The number of studies on efferocytosis in cardiovascular diseases has increased over time. Arteriosclerosis Thrombosis and Vascular Biology published the highest number of articles and was the top co-cited journal. Tabas Ira. was the most prolific researcher and co-cited the most. The most productive countries were the United States and China. Columbia University, Harvard Medical School, and Brigham Women's Hospital were the 3 most productive institutions in the field of research. Keyword Co-occurrence, Clusters, and Burst analyses showed that inflammation, atherosclerosis, macrophages, and phagocytosis appeared with the highest frequency in these studies. CONCLUSION: Multinational cooperation and multidisciplinary intersections are characteristic trends of development in the field, and the immune microenvironment, glycolysis, and lipid metabolism will be the focus of future research.