Macrophage metabolic reprogramming and atherosclerotic plaque microenvironment: Fostering each other?

Macrophages are the central immune cells in atherosclerosis (AS) and play a critical role in the initiation, progression and invasion of atherosclerotic plaques. Metabolic reprogramming is a crucial feature that determines macrophage function and is driven by a combination of intrinsic alterations in macrophages and extrinsic factors such as cytokines acting in the plaque microenvironment. Intrinsic macrophage mechanisms activate signal transduction pathways that change metabolic enzyme activity, and the expression of metabolic regulators. Extrinsic signalling mechanisms involve lipids and cytokines in the microenvironment, promoting and amplifying macrophage metabolic reprogramming. This review describes the intrinsic and extrinsic mechanisms driving macrophage metabolic reprogramming in the AS microenvironment and the interplay of these metabolic rewires in the microenvironment. Moreover, we discuss whether targeting these different pathways to treat macrophage microenvironmental changes can alter the fate of the vulnerable plaques.

Emerging healthy lifestyle factors and all-cause mortality among people with metabolic syndrome and metabolic syndrome-like characteristics in NHANES.

BACKGROUND: The impact of integrated lifestyles on health has attracted a lot of attention. It remains unclear whether adherence to low-risk healthy lifestyle factors is protective in individuals with metabolic syndrome and metabolic syndrome-like characteristics. We aimed to explore whether and to what extent overall lifestyle scores mitigate the risk of all-cause mortality in individuals with metabolic syndrome and metabolic syndrome-like characteristics. METHODS: In total, 6934 participants from the 2007 to 2014 National Health and Nutrition Examination Survey (NHANES) were included. The weighted healthy lifestyle score was constructed based on smoking, alcohol consumption, physical activity, diet, sleep duration, and sedentary behavior information. Generalized linear regression models and restricted cubic splines were used to analyze the association between healthy lifestyle scores and all-cause mortality. ​ RESULTS: Compared to participants with relatively low healthy lifestyle scores, the risk ratio (RR) in the middle healthy lifestyle score group was 0.51 (RR = 0.51, 95% CI 0.30-0.88), and the high score group was 0.26 (RR = 0.26, 95% CI 0.15-0.48) in the population with metabolic syndrome. The difference in gender persists. In females, the RRs of the middle and high score groups were 0.47 (RR = 0.47, 95% CI 0.23-0.96) and 0.21 (RR = 0.21, 95% CI 0.09-0.46), respectively. In males, by contrast, the protective effect of a healthy lifestyle was more pronounced in the high score group (RR = 0.33, 95% CI 0.13-0.83) and in females, the protective effects were found to be more likely. The protective effect of a healthy lifestyle on mortality was more pronounced in those aged < 65 years. Higher lifestyle scores were associated with more prominent protective effects, regardless of the presence of one metabolic syndrome factor or a combination of several factors in 15 groups. What's more, the protective effect of an emerging healthy lifestyle was more pronounced than that of a conventional lifestyle. CONCLUSIONS: Adherence to an emerging healthy lifestyle can reduce the risk of all-cause mortality in people with metabolic syndrome and metabolic syndrome-like characteristics; the higher the score, the more obvious the protective effect. Our study highlights lifestyle modification as a highly effective nonpharmacological approach that deserves further generalization.

Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis.

Non-small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide. A growing number of studies have suggested that long noncoding RNAs (lncRNAs) play a key role in the progression of non-small cell lung cancer (NSCLC). Here, we report a novel lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) that exhibits oncogenic properties in NSCLC. The lncRNA DLGAP1-AS1 and denticleless protein homolog (DTL) presented upregulated expression, but microRNA-193a-5p (miR-193a-5p) showed downregulated expression in cancerous tissues of human lung samples from 48 patients with NSCLC. Partial loss of lncRNA DLGAP1-AS1 reduced malignant cell viability, migration, and invasion but induced apoptosis. Dual-luciferase reporter gene, RNA pull-down and RNA binding protein immunoprecipitation assays demonstrated enrichment of lncRNA DLGAP1-AS1 in miR-193a-5p and Argonaute 2, suggesting that lncRNA DLGAP1-AS1 modulated DTL, a putative target of miR-193a-5p. We also found that restoration of miR-193a-5p rescued NSCLC cell biological functions affected by overexpression of lncRNA DLGAP1-AS1. Silencing lncRNA DLGAP1-AS1 was found to reduce the tumorigenesis of NSCLC cells xenografted into nude mice, which was rescued by DTL overexpression. In conclusion, our study highlights a novel regulatory network of the lncRNA DLGAP1-AS1/miR-193a-5p/DTL axis in NSCLC, providing a potential therapeutic strategy for NSCLC.

Short-term Montreal Cognitive Assessment predicts functional outcome after endovascular therapy.

Background: The previous studies have shown that cognition in patients 4-8 weeks after stroke can predict early functional outcomes after stroke. The analyses of data from the REVASCAT trial proved that stent thrombectomy improves post-morbid wiring test outcomes in patients with AIS compared with drug therapy. However, few studies focus on the relationship between cognitive impairment and functional outcomes in patients undergoing endovascular treatment. Methods: A total of 647 participants registered from stroke centers. Stroke severity was evaluated by National Institutes of Health stroke scale (NIHSS). The functional status was estimated by modified Rankin scale (mRS). The cognitive impairment was assessed by trained neurologists at 14 (±4) and 90 (±7) days after stroke onset using the Montreal Cognitive Assessment (MoCA). A MoCA score of less than 26 was considered post-stroke cognitive impairment (PSCI). Results: A total of 120 Patients who underwent endovascular therapy were included. The PSCI group had higher levels of age, men, educational status, atrial fibrillation, smoking, alcoholism, Alberta Stroke Program Early CT (ASPECT) score of the anterior circulation, and OTP time than the non-PSCI group (p < 0.05). In contrast, the 14-day MoCA score, 14-day NIHSS score, 3-month MoCA score, 3-month NIHSS score, 3-month mRS score, and 3-month EQ5D score were lower in those PSCI patients. The risk predictors of PSCI were age, sex, educational level, atrial fibrillation, smoking, alcoholism, ASPECT Score (anterior circulation), 14-day MoCA score, and 14-day NIHSS score. There were strong relationships between 3-month NIHSS and MoCA (r = -0.483, p < 0.001). Receiver operating characteristic (ROC) curve indicated that 14-day MoCA score, memory, abstraction, visuospatial/executive functions, attention, and language, played a significant role to predict PSCI [area under the curve (AUC) > 0.7]. It had predictive value for the 14-day visuospatial/executive functions to predict 3-month functional outcomes. Conclusion: Early application of the MoCA in different cognitive regions could predict the PSCI and future functional outcomes, which is necessary to screen high-risk patients with poor prognosis and conduct an early intervention.

Comparison of short-term outcomes of mild and moderate hypothermic circulatory arrest in aortic arch surgery: a single center retrospective cohort study.

Background: Aortic arch surgery is one of the major challenges in modern aortic surgery, special cerebral and visceral organ protective strategies are still under progress. Whether mild hypothermic circulatory arrest (Mi-HCA) can be safely used in aortic arch surgery (AAS) is the focus of attention. Methods: From January 2017 to June 2021, a retrospective cohort study of 138 consecutive patients was conducted at Beijing Anzhen Hospital. The study comprised patients who underwent AAS performed by a single surgeon during moderate-to-mild HCA. According to the core temperature at the beginning of circulatory arrest, the patients were divided into three groups: T1 group (n=45; 25.76±0.75 ℃), T2 group (n=43; 28.79±0.81 ℃), T3 group (n=50; 31.46±0.79 ℃). Perioperative clinical data were analyzed to assess the differences between groups. Results: In this cohort, the average durations of the operation, cardiopulmonary bypass (CPB), cross-clamp, circulatory arrest, and selective antegrade cerebral perfusion (SACP) were 6.53±1.48 h, 184.07±56.69 min, 101.04±37.92 min, 23.01±9.86 min, and 27.18±11.52 min, respectively. We observed new postoperative permanent neurological dysfunction (PND) in 12 patients (8.7%) and transient neurological dysfunction in 18 patients (13.04%). The in-hospital mortality rate was 6.52% (n=9). The durations of the operation, CPB, cross-clamp, circulatory arrest, and SACP were significantly reduced in the Mi-HCA group (i.e., T3 group, P<0.001; P<0.001; P<0.001; P=0.002; P<0.001, respectively). The incidence of PND and major adverse events (MAEs) were significantly reduced among the three groups (P=0.025; P=0.035). Multivariate logistic regression analysis models showed that Mi-HCA was an independent protective factor in reducing postoperative MAEs [relative risk (RR) =0.12; 95% confidence interval (CI): 0.02-0.90; P=0.0385]. Conclusions: The short-term outcomes of Mi-HCA combined with SACP in AAS were acceptable. Similarly, the protection of distal organs and the spinal cord was observed compared to the MHCA strategy, and a lower incidence of MAEs was obtained. Current data suggest that the mild hypothermia strategy can be safely applied for AAS.

Exosomes in atherosclerosis: Convergence on macrophages.

As the primary cells of atherosclerotic plaques, macrophages play a central role in the occurrence and progression of atherosclerosis (AS). In recent years, macrophages have received extensive attention as therapeutic targets. Exosomes, as natural nanoparticles, have high biocompatibility and strong targeting ability and have been widely studied as imaging agents and drug carriers. Studies on the relationship between atherosclerotic macrophages and exosomes have been focused on for the past few years. Nevertheless, no complex review has been undertaken in this area. In this review, we summarize in detail the role of macrophages in atherosclerosis, especially their plasticity and phenotypic and distributional heterogeneity. Based on the high correlation between macrophages and the pathological process of atherosclerosis, as well as the targeting of exosomes, we further review the clinical application of targeting macrophage-associated exosomes. We focus on the role of macrophage-associated exosomes in the phenotypic transformation of cells in atherosclerosis, providing a new idea for the clinical application of targeting macrophage-associated exosomes. Finally, we specifically summarize and prospect the diagnosis of macrophage-associated exosomes, such as imaging agent delivery, biomarkers and therapeutic strategies.

Neurofilament Light Chain Protein Is a Predictive Biomarker for Stroke After Surgical Repair for Acute Type A Aortic Dissection.

Background: Although great progress has been made in surgery and perioperative care, stroke is still a fatal complication of acute type A aortic dissection (ATAAD). Serum biomarkers may help assess brain damage and predict patient's prognosis. Methods: From March, 2019 to January, 2020, a total of 88 patients underwent surgical treatment at the Department of Cardiovascular Surgery of Beijing Anzhen Hospital, China, and were enrolled in this study. Patients were divided into two groups according to whether they had suffered a stroke after the operation. Blood samples were collected at 8 time points within 3 days after surgery to determine the level of S100ß, neuron-specific enolase (NSE) and neurofilament light chain protein (NFL). Receiver operating characteristic curves (ROC) were established to explore the biomarker predictive value in stroke. The area under the curve (AUC) was used to quantify the ROC curve. Results: The patient average age was 48.1 ± 11.0 years old and 70 (79.6%) patients were male. Fifteen (17.0%) patients suffered stroke after surgery. The NFL levels of patients in the stroke group at 12 and 24 h after surgery were significantly higher than those in the non-stroke group (all P < 0.001). However, the NSE and S100ß levels did not differ significantly at any time point between the two groups. The predictive value of NFL was the highest at 12 and 24 h after surgery, and the AUC was 0.834 (95% CI, 0.723-0.951, P < 0.001) and 0.748 (95% CI, 0.603-0.894, P = 0.004), respectively. Its sensitivity and specificity at 12 h were 86.7 and 71.6%, respectively. The NFL cutoff value for the diagnosis of stroke at 12 h after surgery was 16.042 ng/ml. Conclusions: This study suggests that NFL is an early and sensitive serum marker for predicting post-operative neurological prognosis of ATAAD patients. Further studies, including large-scale prospective clinical trials, are necessary to test whether the NFL can be used as a biomarker for clinical decision-making.

Mild hypothermic circulatory arrest with selective cerebral perfusion in open arch surgery.

BACKGROUND: This study aimed to evaluate whether the use of mild hypothermic circulatory arrest (HCA) with selective cerebral perfusion (SCP) in open arch procedure provides comparable perioperative results to moderate HCA for patients with dissected or degenerative arch pathologies. METHODS: Between January 2017 and September 2020, a total of 88 consecutive patients (mean age 47±11 years, 71 males) underwent open arch repair under a single surgeon at our institution with mild or moderate systemic hypothermia assisted by unilateral or bilateral SCP. Patients were divided into groups according to the nasopharyngeal temperature at the beginning of HCA: a moderate HCA group (n=47, 53.4%) and a mild HCA group (n=41, 46.6%). The postoperative mortality, morbidity, and visceral organ functions between these groups were analyzed retrospectively. RESULTS: Compared to the moderate HCA group, the mild HCA group had a significantly higher core temperature (nasopharynx: 24.4±0.8 vs. 28.5±2, P<0.001; bladder 25.9±0.9 vs. 30±1.2, P<0.001), and the incidence of major adverse events (MAE) in this group was markedly lower (21.3% vs. 4.9%, P=0.031). No differences were identified between the two groups refer to in-hospital mortality, permanent neurological deficit (PND), temporary neurological deficit (TND), and paraplegia (8.5% vs. 2.4%, P=0.366; 8.5% vs. 0, P=0.120; 6.4% vs. 7.3%, P=1.0; 4.3% vs. 2.4%, P=1.0, respectively). In the moderate HCA group, 6 patients (12.8%) developed acute renal failure needing replacement therapy, which did not occur in the mild HCA group (P=0.028). The duration of ventilator support and intensive care unit stay was shorter in the mild HCA group, as well as a decreased volume of drainage during the first 24 h and reduced platelet transfusion. CONCLUSIONS: The preliminary results of the mild HCA group with SCP applied in open arch repair, mainly in total arch replacement (TAR) and stented elephant trunk (SET) implantation for aortic dissection, were satisfactory. Furthermore, comparable inferior outcomes were obtained with mild HCA compared with that of the conventional moderate HCA strategy. These encouraging surgical and postoperative results favor this more aggressive hypothermia strategy in open arch repair.

Concomitant coronary artery bypass grafting during surgical repair of acute type A aortic dissection affects operative mortality rather than midterm mortality.

BACKGROUND: In this study, we investigated the impact of concomitant coronary artery bypass grafting (CABG) on operative and midterm mortality in patients with acute type A aortic dissection (ATAAD) undergoing surgical repair. METHODS: From January 2012 to December 2014, among 489 patients (mean age: 47.6 ± 10.4 years, 77.1% male) with ATAAD who received surgical repair at our institute, 21 patients (4.3%) underwent concomitant CABG. Isolated aortic repair was performed in the remaining 468 cases (95.7%). Coronary dissection was indicated in 15 patients (Neri classification type B in 2, type C in 13), concomitant coronary artery disease in five and coronary artery compression in one. The follow-up time was 97.3% at 44.1 ± 13.9 months. RESULTS: A total of 44 patients (9%) died from surgery, and operative mortality in the concomitant CABG group was significantly higher than that in the isolated aortic repair group (47.6%, 10/21 vs. 7.3%, 34/468; P < 0.001). Among the 11 survivors in the concomitant CABG group, no deaths occurred during the follow-up. Cox regression indicated that concomitant CABG increased the operative mortality risk by 9.2 times (HR, 9.26; 95% CI, 4.31-19.89; P < 0.001). Although it predicted a 5.2-fold increase in overall mortality (HR, 5.20; 95% CI, 2.55-10.61; P < 0.001), concomitant CABG did not affect midterm death (P = 0.996). CONCLUSIONS: Concomitant CABG carries a significant operative risk in ATAAD patients undergoing surgical repair. However, survivors may benefit from concomitant CABG and had similar midterm mortality compared with the other cases.

Circulating Exosomal circRNAs Contribute to Potential Diagnostic Value of Large Artery Atherosclerotic Stroke.

Large artery atherosclerotic (LAA) stroke is closely associated with atherosclerosis, characterized by the accumulation of immune cells. Early recognition of LAA stroke is crucial. Circulating exosomal circRNAs profiling represents a promising, noninvasive approach for the detection of LAA stroke. Exosomal circRNA sequencing was used to identify differentially expressed circRNAs between LAA stroke and normal controls. From a further validation stage, the results were validated using RT-qPCR. We then built logistic regression models of exosomal circRNAs based on a large replication stage, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic efficacy. Using exosomal circRNA sequencing, large sample validation, and diagnostic model construction revealed that exosomal circ_0043837 and circ_ 0001801were independent predictive factors for LAA stroke, and had better diagnostic efficacy than plasma circRNAs. In the atherosclerotic group (AS), we developed a nomogram for clinical use that integrated the two-circRNA-based risk factors to predict which patients might have the risk of plaque rupture. Circulating exosomal circRNAs profiling identifies novel predictive biomarkers for the LAA stroke and plaque rupture, with superior diagnostic value than plasma circRNAs. It might facilitate the prevention and better management of this disease.

Serum miR-133 as a Potential Biomarker in Acute Cerebral Infarction Patients.

BACKGROUND: The study explores the expression and significance of miR-133 expression in peripheral blood of patients with acute cerebral infarction (ACI), so as to provide new evidence for the diagnosis and treatment of ACI. METHODS: Serum levels of miR-133, interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) were examined using RT-PCR and ELISA, respectively. Pearson's correlation assay was used to analyze the relationship between the level of serum miR-133 and inflammatory factors. Kaplan-Meier method was used to analyze the 10-year survival rate of ACI patients with different levels of miR-133 expression. RESULTS: The level of serum miR-133 in the ACI group was significantly higher than that in healthy group. Mean-while, the level of serum miR-133 in the large infarction group, middle infarction group, small infarction group, and lacunar infarction group was higher than in the healthy group. Moreover, the serum levels of miR-133 in patients with atherosclerotic thrombotic cerebral infarction (AT) and cardioembolic stroke (CE) were significantly higher than those in healthy subjects and small artery occlusive cerebral infarction (SAD) subjects. Serum levels of IL-6, IL-8, CRP and TNF-α in ACI group were significantly higher than those in healthy group. The correlation analysis showed that serum miR-133 was positively correlated with IL-6, IL-8, CRP, and TNF-α in ACI patients. The 10-year survival rate of the low-expression group was significantly higher than that of the high-expression group. CONCLUSIONS: Serum level of miR-133 may indicate the onset and progression of cerebral infarction and may be a potential biomarker for the diagnosis of ACI.

Different hypothermic and cerebral perfusion strategies in extended arch replacement for acute type a aortic dissection: a retrospective comparative study.

BACKGROUND: The optimal hypothermic level in total arch replacement with stented elephant trunk implantation for acute type A aortic dissection (aTAAD) has not been established, and the superiority of unilateral or bilateral cerebral perfusion remains a controversial issue. Therefore, we evaluated the application of moderate hypothermic circulatory arrest (MHCA) with a core temperature of 29 °C and bilateral selective antegrade cerebral perfusion in aTAAD treated by total arch replacement with stented elephant trunk implantation. METHODS: From July 2019 to January 2020, 25 aTAAD patients underwent total arch replacement with stented elephant trunk implantation via MHCA (29 °C) and bilateral selective antegrade cerebral perfusion (modified group). Thirty-six patients treated by the same procedure with MHCA (25 °C) and unilateral selective antegrade cerebral perfusion during this period were selected as controls. RESULTS: There were no differences between the two groups of patients in terms of age, sex, incidence of hypertension, malperfusion, and pericardial effusion, although the incidence of cardiac tamponade was higher in the modified group (control 2.8%, modified 20%; P = 0.038). The lowest mean circulatory arrest temperature was 24.6 ± 0.9 °C in the control group, and 29 ± 0.8 °C in the modified group (P <  0.001). In-hospital mortality was 4.9% (3/61) for the entire cohort (control 8.3%, modified 0; P = 0.262). The incidence of permanent neurologic deficit was 4.9% (control 8.3%, modified 0; P = 0.262). There were no significant differences in the occurrence of temporary neurological deficit, renal failure, and paraplegia between groups. The rate of major adverse events in the modified group was lower (30.6% vs. 4%, P = 0.019). A shorter duration of ventilation and ICU stay was identified in the modified group, as well as a reduced volume of drainage within the first 48 h and red blood cell transfusion. CONCLUSIONS: The early results of MHCA (29 °C) and bilateral selective antegrade cerebral perfusion applied in total arch replacement with stented elephant trunk implantation for aTAAD were acceptable, providing similar inferior cerebral and visceral protection compared with that of the conventional strategy. A higher core temperature may account for the shorter duration of ventilation and ICU stay, as well as a reduced volume of drainage and red blood cell transfusion.

Sun's total arch replacement and stent elephant trunk with modified branch-first technique for patients with Stanford type A aortic dissection.

BACKGROUND: Stanford type A aortic dissection (STAAD) is a critical cardiovascular disease, and surgical procedure is the first-choice treatment. The classical surgical procedure still leads to a high mortality rate and neurological complications. In this study, we introduce a new modified Sun's procedure and investigate the association between the branch-first technique and the postoperative outcomes of patients with STAAD. METHODS: A total of 108 consecutive patients with STAAD who underwent arch replacement and stent elephant trunk procedure at Beijing Anzhen Hospital between July, 2017 and November, 2018 were included in the analysis. The patients were divided into two groups: the branch-first group and the classic group. The branch-first group and the classic group comprised 24 patients (22.2%) and 84 patients (77.8%), respectively. RESULTS: Patients in the branch-first group had a significantly shorter cardiopulmonary bypass (CPB) duration (172.4±29.9 vs. 194.9±47.4 min; P=0.035), Intensive care unit (ICU) stay [17.0 (14.6-38.2) vs. 42.1 (19.7-87.2) hours; P<0.001], and mechanical ventilation time [15.5 (11.9-40.0) vs. 19.0 (17.0-45.6) hours; P=0.018] than patients in the classic group. The branch-first was associated with a reduction in postoperative neurological complications in all models. CONCLUSIONS: The benefits of the branch-first technique, including lower CPB duration, better bilateral cerebral perfusion, and higher nasopharyngeal temperature during hypothermic arrest, contributed to a shortened recovery time for patients after surgery.

The use of cIMT as a predictor of postoperative stroke in patients undergoing surgical repair of acute type a aortic dissection.

BACKGROUND: Acute type A aortic dissection (ATAAD) is a life-threatening condition that requires surgical intervention. Stroke remains an extremely serious adverse outcome that can occur in ATAAD patients undergoing aortic arch repair, leading to higher rates of patient mortality and decreased postoperative quality of life. In the present study, we sought to determine whether carotid intima-media thickness (cIMT) is a reliable predictor of postoperative stroke risk. MATERIALS AND METHODS: This was a prospective study of 76 patients with ATAAD undergoing aortic arch repair. For all patients, cIMT was determined preoperatively through a Doppler-based method. Incidence of different forms of neurological dysfunction, including temporary neurological dysfunction (TND) and stroke, was monitored in these patients, and the relationship between cIMT and stroke incidence was assessed using a receiver-operating characteristic (ROC) curve. Prognostic variables associated with stroke risk were further identified through univariate and multivariate analyses. RESULTS: A total of 26/76 (34.2%) patients in the present study suffered from neurological dysfunction, of whom 16 (21.0%) suffered from TND and 10 (13.2%) suffered a stroke. The remaining 50 patients (65.8%) did not suffer from neurological dysfunction. The cIMT values in the stroke, TND, and neurological dysfunction-free patients in this study were 1.12 ± 0.19 (mm), 0.99 ± 0.13 (mm), and 0.87 ± 0.13 (mm), respectively. A total of 4 patients in this cohort died during the study, including 1 in the TND group and 3 in the stroke group. An ROC curve analysis indicated that cIMT could predict stroke with an area under the curve value of 0.844 (95% CI, 0.719-0.969; p < 0.001). A multivariate analysis revealed that cIMT > 0.9 mm was independently associated with stroke risk (p = 0.018). CONCLUSION: We found that cIMT can be used to predict postoperative stroke risk in ATAAD patients undergoing aortic arch repair, with a cIMT > 0.9 mm coinciding with increased stroke risk in these patients. TRIAL REGISTRATION: ChiCTR1900022289. Date of registration 4 April 2019 retrospectively registered.

K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages.

Inflammation, especially involving the NLRP3 inflammasome, is critical to atherosclerotic plaque formation. Enhanced autophagy can inhibit the development of atherosclerosis, and recent studies have revealed that NLRP3 inflammasome can be degraded by autophagy in atherosclerosis. In the present study, we established a foam-cell model to investigate the impact of oxidized low density lipoproteins (ox-LDLs) on autophagy and the inflammasome in atherosclerosis-related inflammation. We observed that ox-LDLs activated NLRP3 inflammasomes in macrophages and restricted autophagy in a time-and dose-dependent manner. We further observed through immunoprecipitation and siRNA knockdown that autophagic degradation of the NLRP3 inflammasome is dependent on K63 polyubiquitation of its NLRP3 subunit and subsequent binding by the adaptor protein p62. Our findings uncover a mechanism by which autophagy inhibits inflammation in atherosclerosis and the role of K63 in that process.

Renal malperfusion affects operative mortality rather than late death following acute type A aortic dissection repair.

OBJECTIVE: The aim of our study was to assess how much renal malperfusion increases the risk of early and late mortality in patients with acute type A aortic dissection (ATAAD) undergoing surgical repair. METHODS: This study included 218 patients with ATAAD undergoing surgical repair using the total arch replacement and frozen elephant trunk technique. Mean age was 47.8 ± 10.7 years and 170 were male (78.0%). Based on clinical symptoms and computed tomographic angiography (CTA) findings, 48 patients were diagnosed with preoperative renal malperfusion (22.0%). Clinical data were compared between two groups. The impact of renal malperfusion on operative and late mortality were evaluated with Cox regression. RESULTS: Patients with renal malperfusion experienced significantly higher incidences of persistent postoperative acute kidney injury (AKI; 10/48, 20.8% vs 7/170, 4.1%; p < 0.001) and transient AKI (10/48, 20.8% vs 8/170, 4.7%; p = 0.001) as well as operative mortality (22.9%, 11/48 vs 8.3%, 14/170; p = 0.023). Five-year survival was significantly lower in the renal malperfusion group (72.9% vs 87.0%, p = 0.003). Renal malperfusion was the risk factor for operative mortality (hazard ratio, HR, 2.74; 95% CI, 1.07-6.99; p = 0.035) and overall mortality (HR, 2.64; 95% CI, 1.23-5.67; p = 0.013) but did not predict late death (HR, 2.46; 95% CI, 0.65-9.35; p = 0.187). CONCLUSION: Renal malperfusion increases the risk of operative mortality by 3 times but did not affect late death in patients undergoing acute type A dissection repair.

Fucoidan Inhibits NLRP3 Inflammasome Activation by Enhancing p62/SQSTM1-Dependent Selective Autophagy to Alleviate Atherosclerosis.

NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation contributes to the progression of atherosclerosis, and autophagy inhibits inflammasome activation by targeting macrophages. We investigated whether fucoidan, a marine sulfated polysaccharide derived from brown seaweeds, could reduce NLRP3 inflammasome activation by enhancing sequestosome 1 (p62/SQSTM1)-dependent selective autophagy to alleviate atherosclerosis in high-fat-fed ApoE-/- mice with partial carotid ligation and differentiated THP-1 cells incubated with oxidized low-density lipoprotein (oxLDL). Fucoidan significantly ameliorated lipid accumulation, attenuated progression of carotid atherosclerotic plaques, deregulated the expression of NLRP3 inflammasome, autophagy receptor p62, and upregulated microtubule-associated protein light chain 3 (LC3)-II/I levels. Transmission electron microscopy and GFP-RFP-LC3 lentivirus transfection further demonstrated that fucoidan could activate autophagy. Mechanistically, fucoidan remarkably inhibited NLRP3 inflammasome activation, which was mostly dependent on autophagy. The inhibitory effects of fucoidan on NLRP3 inflammasome were enhanced by autophagy activator rapamycin (Rapa) and alleviated by autophagy inhibitor 3-methyladenine (3-MA). Fucoidan promoted the colocalization of NLRP3 and p62. Knockdown of p62 and ATG5 by small interfering RNA significantly reduced the inhibitory effects of fucoidan treatment on NLRP3 inflammasome. The data suggest that fucoidan can inhibit NLRP3 inflammasome activation by enhancing p62/SQSTM1-dependent selective autophagy to alleviate atherosclerosis.

MicroRNA-155 promotes the ox-LDL-induced activation of NLRP3 inflammasomes via the ERK1/2 pathway in THP-1 macrophages and aggravates atherosclerosis in ApoE-/- mice.

BACKGROUND: Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation can induce the secretion of IL-1ß and IL-18 and after promoting the development of atherosclerosis. MiR-155 is an important microRNA that modulates inflammation in atherosclerosis, but the role of miR-155 in the regulation of the NLRP3 inflammasome is still unknown. METHODS: The atherosclerosis model was set up using ApoE-/- mice, and the lentiviral vector (LV) was used to interfere the expression of miR-155. HE stains was used for plaque morphology, immunohistochemistry (IHC) and western blot were used for protein expression quantification. We used oxidized low-density lipoprotein (ox-LDL) to incubate PMA-preprocessed THP-1 macrophages and detected NLRP3 inflammasome activation and ERK1/2 phosphorylation by western blot and Enzyme-linked immunosorbent assay. RESULTS: HE stains showed that the intravascular plaques in the miR-155-up group were remarkably increased, compared with negative control (NC) group. Results of IHC showed that the expression of caspase-1 and IL-1ß in the miR-155-up group was the highest of four groups, consist with the Western blot analysis. The results of in vitro experiment show that ox-LDL promoted NLRP3 inflammasome activation and ERK1/2 phosphorylation. Blocking the ERK1/2 pathway could inhibit ox-LDL-induced NLRP3 inflammasome activation. Moreover, we found that the overexpression of miR-155 promoted the activation of the ox-LDL-induced NLRP3 inflammasome, which could also be blocked by the ERK inhibitor U0126. CONCLUSIONS: MiR-155 aggravates the carotid AS lesion in ApoE-/- mice and exerts a regulatory effect on NLRP3 inflammasome activation in ox-LDL-induced macrophages via the ERK1/2 pathway.

PTPN22 Gene Polymorphisms Are Associated with Susceptibility to Large Artery Atherosclerotic Stroke and Microembolic Signals.

Large artery atherosclerotic stroke (LAAS) is the most common ischemic stroke (IS) subtype, and microemboli may be clinically important for indicating increased risk of IS. The inflammatory process of atherosclerosis is well known, and lymphoid phosphatase (Lyp), which is encoded by the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene, plays an important role in the inflammatory response. Our study was intended to evaluate the relationship between PTPN22 gene and LAAS and microembolic signals (MES). Three loci of the PTPN22 gene (rs2476599, rs1217414, and rs2488457) were analyzed in 364 LAAS patients and 369 control subjects. A genotyping determination was performed using the TaqMan assay. The G allele of rs2488457 might be related to a higher risk for developing LAAS and MES (odds ratio (OR) = 1.456, 95% confidence interval (CI) 1.156-1.833, P = 0.001; OR = 1.652, 95% CI 1.177-2.319, P = 0.004, respectively). In the LAAS group, the prevalence of the GTG haplotype was higher (P < 0.001) and the prevalence of the GCC haplotype was lower (P = 0.001). An interaction analysis of rs2488457 with smoking showed that smokers with the CG/GG genotypes had a higher risk of LAAS, compared to nonsmokers with the rs2488457 CC genotype (OR = 2.492, 95% CI 1.510-4.114, P < 0.001). Our research indicated that the PTPN22 rs2488457 might be related to the occurrence of LAAS and MES in the Han Chinese population. In addition, the rs2488457 polymorphism and the environmental factor of smoking jointly influenced the susceptibility of LAAS.

Plasma Osteoprotegerin Correlates with Stroke Severity and the Occurrence of Microembolic Signals in Patients with Acute Ischemic Stroke.

BACKGROUND: Instability of atherosclerotic plaques is associated with the occurrence of stroke. Microembolic signals (MESs) are an indicator of unstable plaque. A relationship between plasma osteoprotegerin (OPG) and ischemic stroke has already been identified. The aim of this study was to investigate whether plasma OPG levels have a relationship with MESs and to evaluate the feasibility of OPG as a biomarker of stroke severity and occurrence of MESs. METHODS: Our study consisted of 127 patients with large artery atherosclerosis stroke and 56 controls. Patients were classified into subgroups based on stroke severity and the occurrence of MESs. MES-monitoring was performed for 60 min using transcranial Doppler within 72 h of stroke onset. Stroke severity at admission was assessed by the National Institutes of Health Stroke Scale. RESULTS: Plasma OPG levels were significantly associated with stroke, MESs, and stroke severity at admission (adjusted OR [95% CI]: 1.002 [1.001-1.003] p < 0.001; 1.002 [1.001-1.003] p = 0.001; 1.001 [1.000-1.002] p = 0.028). When plasma OPG levels were used to determine the stroke severity, the area under the receiver-operating characteristic curve (AUC) was 0.734 (95% CI: 0.625-0.843) based on a cutoff value of 1998.44 pg/ml; the sensitivity and specificity of this test were 80.6% and 65.6%, respectively. Furthermore, when the levels of OPG were used to distinguish the presence of MESs, the AUC was 0.766 (95% CI: 0.672-0.860); the cutoff value was 2107.91 pg/ml. The sensitivity of this cutoff value was 68.8% and the specificity was 73.7%. CONCLUSIONS: Plasma OPG levels correlate with stroke severity and the occurrence of MESs.