Coronary computed tomography angiography-derived total coronary plaque burden associated with subsequent cardiovascular outcomes following percutaneous coronary intervention.

OBJECTIVE: To investigate the association of coronary plaque burden variables derived from coronary computed tomography angiography (CCTA) before patients underwent their first percutaneous coronary intervention (PCI) procedure and major adverse cardiovascular events (MACEs) after PCI. METHODS: Patients who underwent CCTA before their first PCI were included retrospectively. A radiologist and a cardiologist analyzed CCTA images on a dedicated workstation. The coronary plaque burden variables included total plaque volume, total percent atheroma volume, volumes and fractions of total low-attenuation plaque, total fibrous plaque, and total calcified plaque. The primary outcomes were MACEs, a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and unscheduled coronary revascularization. RESULTS: A total of 230 patients were included in the final analysis. During a median follow-up of 4.8 years, 67 MACEs occurred. Total plaque volume, total percent atheroma volume, volumes of total low-attenuation plaque and total fibrous plaque but not their fractions were independent predictors for MACEs. Compared with the first tertiles, the hazard ratio of the third tertile of total plaque volume, total percent atheroma volume, total low-attenuation plaque volume, and total fibrous plaque volume were 2.06 (95% CI: 1.03-4.15), 2.15 (95% CI: 1.02-4.51), 3.04 (95% CI: 1.45-6.36), and 2.23 (95% CI: 1.11-4.46), respectively. Neither total calcified plaque volume nor fraction was associated with MACEs independently. CONCLUSION: Selected pre-PCI CCTA-derived variables, including total percent atheroma volume, volumes of total plaque, total low-attenuation plaque and total fibrous plaque, were significantly associated with MACEs after PCI, suggesting that CCTA before PCI reveals the residual risk after revascularization. CLINICAL RELEVANCE STATEMENT: The coronary plaque burden variables derived from coronary computed tomography angiography before percutaneous coronary intervention are independently associated with major adverse cardiovascular events, which could be instrumental in optimizing patient management. KEY POINTS: Coronary plaque burden is associated with cardiovascular events in patients with coronary artery disease. Selected total plaque burden variables derived from coronary computed tomography angiography before percutaneous coronary intervention were associated with poor prognosis. Routine coronary computed tomography angiography before percutaneous coronary intervention might be helpful in reducing future risks.

Obesity, birth weight, and lifestyle factors for frailty: a Mendelian randomization study.

Obesity, birth weight and lifestyle factors have been found associated with the risk of frailty in observational studies, but whether these associations are causal is uncertain. We conducted a two-sample Mendelian randomization study to investigate the associations. Genetic instruments associated with the exposures at the genome-wide significance level (p < 5 × 10-8) were selected from corresponding genome-wide association studies (n = 143,677 to 703,901 individuals). Summary-level data for the frailty index were obtained from the UK Biobank (n = 164,610) and Swedish TwinGene (n = 10,616). The ß of the frailty index was 0.15 (p = 3.88 × 10-9) for 1 standard deviation increase in the prevalence of smoking initiation, 0.19 (p = 3.54 × 10-15) for leisure screen time, 0.13 (p = 5.26 × 10-7) for body mass index and 0.13 (p = 1.80 × 10-4) for waist circumference. There was a suggestive association between genetically predicted higher birth weight and moderate-to-vigorous intensity physical activity with the decreased risk of the frailty index. We observed no causal association between genetically predicted age of smoking initiation and alcoholic drinks per week with the frailty index. This study supports the causal roles of smoking initiation, leisure screen time, overall obesity, and abdominal obesity in frailty. The possible association between higher birth weight, proper physical activity and a decreased risk of frailty needs further confirmation.

Lipoprotein(a) is a new prognostic factor in patients with psoriasis and coronary artery disease: a retrospective cohort study.

BACKGROUND: The prognostic value of lipoprotein (Lp) (a) in patients who have suffered from coronary artery disease (CAD) has not been fully studied, and the results are inconsistent. This study was conducted to evaluate whether increased Lp(a) concentrations cause differences in clinical adverse outcomes in patients with psoriasis who have already suffered from CAD. METHODS: This retrospective cohort study included consecutive patients with psoriasis and CAD between January 2017 and May 2022 in our hospital. The clinical records were collected, and comparisons were made between patients in the low Lp(a) and high Lp(a) groups. Cox proportional hazard analysis and log-rank tests were used to evaluate the association between variables. RESULTS: Among 295 patients, 148 patients were in the low Lp(a) group, and 147 were in the high Lp(a) group. These two groups did not differ significantly in age, gender or body mass index. Compared with the low Lp(a) group, the levels of platelet counts (P = 0.038) and high sensitivity C reactive protein (P = 0.012) were higher in the high Lp(a) group. Patients in the high Lp(a) group had higher total cholesterol levels (P = 0.029) and lower triglyceride levels (P = 0.037). Among the whole cohort, clinical adverse events were not correlated with Lp(a) concentrations after a median follow-up of 3 years. However, in the subgroup analysis, there were significant differences in all-cause death (log rank P = 0.036) and rehospitalization (log rank P = 0.037) between the two groups in patients with diabetes; a difference in rehospitalization (log rank P = 0.042) was also found between the two groups in men. CONCLUSIONS: In patients with psoriasis and CAD, high levels of Lp(a) were related to a poor prognosis, especially in patients with diabetes and in men. These results will provide valuable information for the risk stratification of patients with psoriasis and CAD.

Fibrinogen is Associated with Clinical Adverse Events in Patients with Psoriasis and Coronary Artery Disease.

Purpose: The presence of elevated fibrinogen levels is associated with cardiovascular disease. However, whether fibrinogen level is associated with adverse clinical events in patients with psoriasis and coronary artery disease (CAD) is unknown. This study aimed to investigate the relationship between fibrinogen levels and cardiovascular adverse events in these patients. Patients and Methods: This retrospective cohort study collected consecutive patients with psoriasis and CAD between January 2017 and May 2022 in our hospital. The clinical records were collected, and comparisons were made between groups. The Cox regression analysis and Kaplan-Meier survival analysis were used to evaluate the association between variables. Results: Of the 267 participants, one hundred and forty-seven patients (55.1%) had elevated fibrinogen levels. Compared with patients in low fibrinogen group, white blood cell and platelet counts and high-sensitivity C-reactive protein levels were higher, whereas the left ventricular ejection fraction was lower in patients in high fibrinogen group. After a median follow-up of 35.5 months, the incidence of major adverse cardiovascular events (MACEs) was higher in patients in high fibrinogen group compared with patients in low fibrinogen group (31.4% vs 16.4%, p = 0.013). The Kaplan-Meier survival curves showed the same trend (log rank p = 0.020). Subgroup analysis revealed a positive association between elevated fibrinogen levels and MACEs in patients aged <60 years (log-rank p = 0.013), those with diabetes (log-rank p = 0.027), and those who were not admitted for acute cardiovascular syndrome (log-rank p = 0.015). Conclusion: Elevated fibrinogen levels were associated with adverse clinical events in patients with psoriasis and CAD, especially among patients aged <60 years, those with diabetes, and those not admitted for acute cardiovascular syndrome.

Serum total bilirubin and one-year prognosis of patients with coronary artery disease and psoriasis.

To evaluate the potential predictive value of total bilirubin (TBIL) for one-year prognosis in patients with coronary artery disease (CAD) and psoriasis. 278 psoriasis patients who underwent coronary angiography and were diagnosed as CAD were recruited. Baseline TBIL was measured at admission. Patients were divided into three groups according to the third tertiles of TBIL. The coronary angiography showed that lower TBIL was associated with the severity of lesion calcification. After a mean follow-up of 315 days, major adverse cardiac and cerebrovascular events (MACCEs) were reported in 61 patients. Compared with patients with higher TBIL tertiles, the incidence of MACCEs increased significantly in patients with middle and lower TBIL tertiles. The incidence of MACCEs in one-year follow-up was significantly different between higher and lower tertiles. The findings indicate that decreased TBIL is a potential predictor of poor prognosis in patients with psoriasis and CAD.

Effects of Metabolic Syndrome on Cardiovascular Outcomes of Psoriatic Patients with Coronary Artery Disease: A Single Center Retrospective Cohort Study.

Background: Psoriasis is associated with an increased prevalence of cardiovascular risk factors, including metabolic syndrome (MetS). To date, it is unclear whether MetS causes differences in cardiovascular outcomes in psoriatic patients with coronary artery disease. Methods: We conducted a retrospective cohort study to determine the effects of MetS in psoriatic patients with coronary artery disease. Comparisons were made between patients with and without MetS. Cox regression analysis and Kaplan-Meier survival analysis were used to evaluate the association between variables. Results: Of the 307 psoriatic patients with coronary artery disease, 94 met criteria (30.6%) for MetS. Individuals with MetS were more likely to be female (p <0.001). Levels of platelet counts and high-sensitivity C-reactive protein were higher in the MetS group (p = 0.038 and 0.005, respectively). After a mean follow-up of 35.32 months, major adverse cardiovascular events (MACEs) and non-fatal myocardial infarction were more likely in the MetS than the non-MetS group (33.3% vs 20.6%, p = 0.02; 26.4% vs 15.7%, p = 0.032, respectively). Kaplan-Meier estimates showed the same trend. Cox regression analysis showed that MetS (hazard ratio 1.738; 95% confidence interval 1.045-2.891; p = 0.033) and left ventricular ejection fraction (hazard ratio 0.968; 95% confidence interval 0.945-0.991; p = 0.006) were associated with an increased risk of MACEs. Conclusion: In psoriatic patients with coronary artery disease, MetS independently predicted MACEs. In addition, left ventricular ejection fraction was negatively associated with an increased risk of MACEs. To reduce the cardiovascular disease risk, it is necessary to increase awareness of MetS in psoriatic patients with coronary artery disease.

The efficacy of intraoperatie continuous glucose monitoring in patients undergoing liver transplantation: a study protocol for a prospective randomized controlled superiority trial.

BACKGROUND: The high incidence of intraoperative glucose dysregulations in liver transplantation (LT) is related to the lack of highly orchestrated control of intraoperative blood glucose. Glucose monitoring based on a single arterial blood gas test can only provide a simple glucose profile and is insufficient in monitoring intraoperative glycemic variability (GV), which is not conducive to controlling GV and may have a lag in the management of hyper/hypoglycemia. Continuous glucose monitor (CGM), which has been successfully applied in the management of chronic disease in diabetes, provides more detailed blood glucose records and reflect GV parameters such as coefficient of variation (CV%). However, its effectiveness and accuracy for guiding blood glucose management in major surgeries remains unclear. METHODS: This is a single-center, randomized, controlled, superiority trial. One hundred and eighty patients scheduled for orthotopic LT will be recruited and randomized into two groups. All patients are monitored for intraoperative glucose using CGM combined with arterial blood gas (ABG). In the intervention group (group CG), ABG will be performed when CGM value is < 6.1 mmol/L or > 10.0 mmol/L, or the rate of change of CGM value > 1.67 mmol/(L·min). In the control group (group G), intraoperative ABG tests will be performed every 2 h, and the frequency of ABG tests will be adjusted based on the previous arterial glucose result. Patients in both groups will have their blood glucose adjusted according to arterial glucose values and a uniform protocol. Surgical and other anesthetic management is completed according to standard LT practices. DISCUSSION: This study intends to investigate the effectiveness of CGM-based intraoperative glucose management and its impact on the prognosis of LT patients by comparing the GV, mean glucose values, and the incidence of hypo/hypoglycemic events guided by the above two glucose monitoring methods. TRIAL REGISTRATION: This study is registered at www.chictr.org.cn on January 4, 2022, under the registration number ChiCTR2200055236.

Sirt6 mediates antioxidative functions by increasing Nrf2 abundance.

Oxidative stress caused by excess ROS often leads to cellular macromolecule damage and eventually causes various biological catastrophes. Sirt6, a member of the mammalian homolog family of yeast Sir2 NAD+-dependent histone deacetylases, regulates multiple biological processes. Sirt6 exerts antioxidative functions by enhancing DNA repair and DNA end resection. In our study, we found that Sirt6 expression was induced by H2O2 and paraquat (PQ) in cells. When exposed to PQ, the Sirt6+/- C57BL/6 mice showed more serious liver damage and lower survival rate than the Sirt6+/+ mice. The Nrf2 protein levels and the mRNA levels of its target genes in mouse tissues were decreased by Sirt6 deficiency, and Sirt6 overexpression increased the Nrf2 protein content. Moreover, the endogenous H2O2 levels were increased in the tissues of Sirt6-deficient mice and were decreased in Sirt6 overexpression cells. Then, we found that Nrf2 was degraded faster in the Sirt6-deficient mouse embryonic fibroblasts (MEFs) than in the wild type MEFs and that Sirt6 enhanced the protein accumulation of Nrf2 in the nucleus. Lastly, we found that Sirt6 interacted with Nrf2 in co-IP and GST pull-down assays and that Sirt6 overexpression decreased the binding of Nrf2 to Keap1. Taken together, the results of the present study suggest that Sirt6 exerts antioxidative functions by increasing the Nrf2 protein level via Keap1-mediated regulation.

Application of online case-based learning in the teaching of clinical anesthesia for residents during the COVID-19 epidemic.

OBJECTIVE: COVID-19 prevention and control demand a reduction in crowd gathering, which has a significant impact on traditional teaching and offline case-based learning (CBL). In order to mitigate the impact of the COVID-19 outbreak on clinical teaching, we aimed to compare the effects of an online CBL with traditional teaching model on learning outcomes of anesthesia residents. METHODS: Residents rotated in the Department of Anesthesiology in Beijing Tsinghua Changgung Hospital from January 2020 to February 2021 were included in Group W (n = 19), which implemented the W-CBL teaching model. The performance of residents was evaluated with theory test and 2 survey questionnaires (A and B) were conducted after 1 month of rotating. All 20 residents rotating in the Department of Anesthesiology at our hospital from January 2018 to December 2019 were included in Group C, which implemented the traditional teaching model. Their examination results were acquired through the teaching files and survey questionnaire (A) were administered through WeChat. RESULTS: During the 1-month rotation, a total of 10 cases were discussed in Group W. The average score for theory test was higher in Group W than that in Group C (84.57 ± 4.87 vs. 79.35 ± 3.70, P = 0.001). The satisfaction rate was also in favor of Group W regarding to clinical thinking, communication skills, learning interest and self-learning ability (P < 0.05). CONCLUSIONS: Online CBL based on WeChat platform is an effective and acceptable teaching strategy in comparison to lecture-based learning (LBL) among residents embarking on clinical anesthesia courses.

Risk Factors and Prognosis of New-Onset Chronic Kidney Disease Following Orthotopic Liver Transplantation: A Retrospective Case-Control Study.

BACKGROUND We have undertaken this investigation to explore the perioperative risk factors of new-onset chronic kidney disease (NOCKD) after orthotopic liver transplantation (OLT), and to provide an early prediction model for the screening of NOCKD high-risk populations. MATERIAL AND METHODS A retrospective case-control study was performed in adult recipients who received OLT in our center between January 2018 and January 2020. Perioperative data were collected using the center's electronic medical record system. Logistics regression analysis was used to determine risk factors for NOCKD within 1 year following OLT. Kaplan-Meier and log-rank tests were used to evaluate the 1-year survival of recipients with NOCKD or without NOCKD. RESULTS A total of 174 patients were included in this study, and 29 patients developed NOCKD after OLT. Logistic multivariate regression analysis showed that preoperative diabetes, high model for end-stage liver disease (MELD) score, postoperative acute kidney injury (AKI), and postoperative renal replacement therapy (RRT) were independent risk factors for NOCKD 1 year after OLT. The 1-year survival rate of NOCKD recipients waas significantly lower than that of patients who did not receive NOCKD. CONCLUSIONS Diabetes mellitus, MELD score, postoperative AKI, and requirement for postoperative RRT are independent risk factors for NOCKD after OLT, which may have great potential for personalized decision making and predicting the 1-year postoperative mortality of the recipient.

Different treatment options for Takayasu arteritis patients with moderate-to-severe aortic regurgitation: long-term outcomes.

OBJECTIVES: To determine the prognosis of Takayasu arteritis (TA) patients with moderate-to-severe aortic regurgitation treated with surgical vs conservative treatment and to identify independent prognostic factors of long-term outcomes. METHODS: Between January 2002 and January 2017, 101 consecutive TA patients with moderate-to-severe aortic regurgitation treated with either surgical (n = 38) or conservative (n = 63) treatments were investigated in this retrospective observational case-control study. The primary end point was all-cause mortality, and the secondary end point comprised the combined end points of death, non-fatal stroke and cardiac events (non-fatal myocardial infarction and congestive heart failure). Propensity score matching was used to reduce the bias of baseline risk factors. RESULTS: The unadjusted all-cause 10-year mortality in the conservative group was increased compared with the surgical group (28.2% vs 7.4%; log-rank P = 0.036), and the combined end points showed the same trend (52.1% vs 25.3%; log-rank P = 0.005). After an adjustment of baseline risk factors, the conservative treatment was associated with reduced survival rates of both all-cause mortality [hazard ratio (HR): 8.243; 95% CI: 1.069, 63.552; P = 0.007] and combined end points (HR: 6.341; 95% CI: 1.469, 27.375; P = 0.002). Conservative treatment (HR: 3.838, 95% CI: 1.333, 11.053; P = 0.013) and left ventricular end-diastolic diameter (HR: 1.036, 95% CI: 1.001, 1.071; P = 0.042) were risk factors for increased combined end points. CONCLUSION: Surgical treatment improves the outcomes of patients with moderate-to-severe aortic regurgitation due to TA. The dilated left ventricle indicated a worse prognosis.

Association of interleukin-6 and interleukin-10 expression, gene polymorphisms, and Takayasu arteritis in a Chinese Han population.

Takayasu arteritis (TA) is a chronic inflammatory disease. Interleukin (IL)-6 and IL-10 are important cytokines involved in the immune response of TA in some ethnicities. We investigated whether the single-nucleotide polymorphism (SNP) of IL-6 and IL-10 genes and their expressions were associated with TA in a Chinese Han population. One hundred eighty-four TA patients and 235 healthy controls (HC) were recruited. DNA and RNA were extracted from peripheral blood cells. Genotyping of IL-6 and -10 was performed using polymerase chain reaction-ligase detection reaction (PCR-LDR). The mRNA levels of IL-6 and IL-10 were semi-quantified using reverse transcription polymerase chain reaction (RT-PCR) and real-time polymerase chain reaction (real-time PCR). Plasma levels of them were examined by enzyme-linked immunosorbent assay (ELISA). The mRNA levels of IL-6 in active phase of TA were higher than those in stable phase (p = 0.015); the IL-10 in active phase was lower compared with stable phase (p = 0.046). Plasma levels of IL-6 in TA were higher than those in HC (p = 0.024). Plasma levels of IL-10 showed no difference between the two groups (p = 0.264). Plasma levels of IL-6 in active phase were increased than those in stable phase (p = 0.043) while those of IL-10 were decreased in active phase (p = 0.041). We found no significant differences between TA and HC in the frequency of any of the variations in the SNPs of IL-6 and IL-10 genes. The expression levels of both cytokines were associated with the disease status, indicating that they may serve as potential biomarkers for monitoring disease activity.

Epigenetic regulation of NKG2D ligands is involved in exacerbated atherosclerosis development in Sirt6 heterozygous mice.

Sirt6 is a member of the class III histone deacetylase family which is associated with aging and longevity. Sirt6 deficient mice show an aging-like phenotype, while male transgenic mice of Sirt6 show increased longevity. Sirt6 acts as a tumor suppressor and deficiency of Sirt6 leads to cardiac hypertrophy and heart failure. Whether Sirt6 is involved in atherosclerosis development, the major cause of cardiovascular diseases, is unknown. We found that the expression of Sirt6 is lower in human atherosclerotic plaques than that in controls. When Sirt6(+/-)ApoE(-/-) and ApoE(-/-) mice are fed with high fat diet for 16 weeks, Sirt6(+/-)ApoE(-/-) mice show increased plaque fromation and exhibit feature of plaque instability. Furthermore, Sirt6 downregulation increases expression of NKG2D ligands, which leads to increased cytokine expression. Blocking NKG2D ligand almost completely blocks this effect. Mechanistically, Sirt6 binds to promoters of NKG2D ligand genes and regulates the H3K9 and H3K56 acetylation levels.

Hepatic Oncostatin M Receptor ß Regulates Obesity-Induced Steatosis and Insulin Resistance.

The liver is an essential insulin-responsive organ that is critical for maintaining glucose homeostasis and lipid metabolism. Oncostatin M receptor ß chain (OSMRß) is implicated in adipose tissue- and immune cell-mediated metabolic regulation. However, the role of hepatocyte-derived OSMRß in metabolic disorders remains unclear. Here, we report on the central role of OSMRß in the protection against obesity and deregulation of glucose and lipids. We observed significantly varied expression levels of OSMRß in hepatic tissues in both human samples and mouse models of nonalcoholic fatty liver disease. Mice lacking either whole-body or hepatic OSMRß displayed exacerbated diet-induced insulin resistance, hepatic steatosis, and inflammation, both in diet-induced and genetically (ob/ob) obese mice. These adverse effects were markedly attenuated by hepatocyte-specific overexpression of OSMRß. Mechanistically, we showed that OSMRß phosphorylates and activates the Janus kinase 2 (JAK2)/STAT3 signaling pathway in the liver. More importantly, the liver-restricted overexpression of STAT3 rescued glucose tolerance and ameliorated hepatic steatosis and inflammation in OSMRß knockout mice, whereas OSMRß overexpression failed to protect against hepatic steatosis, insulin resistance, and hepatic inflammation in STAT3-deficient mice. Thus, activation of STAT3 is both sufficient and required to produce OSMRß-mediated beneficial effects. In conclusion, hepatic OSMRß expression alleviates obesity-induced hepatic insulin resistance and steatosis through the activation of JAK2/STAT3 signaling cascades.

Neuron-Specific Tumor Necrosis Factor Receptor-Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke.

Neuronal death after ischemic stroke involves multiple pathophysiological events, as well as a complex molecular mechanism. Inhibiting a single therapeutic target that is involved in several ischemic signaling cascades may be a promising strategy for stroke management. Here, we report the versatile biological roles of tumor necrosis factor receptor-associated factor 3 (TRAF3) in ischemic stroke. Using several genetically manipulated mouse strains, we also demonstrated that TRAF3 inhibition can be neuroprotective. TRAF3 expression, which is robustly induced in response to ischemia/reperfusion (I/R) injury, was detected in neurons. Overexpression of TRAF3 in neurons led to aggravated neuronal loss and enlarged infarcts; these effects were reversed in TRAF3-knockout mice. Neuronal TRAF3 also contributed to c-Jun kinase-, nuclear factor κB- and Rac-1-induced neuronal death, inflammation, and oxidative stress. Mechanistically, we showed that TRAF3 interacts with transforming growth factor-ß-activated kinase 1 (TAK1) and potentiates phosphorylation and activation of TAK1. Phosphorylated TAK1 sequentially initiated activation of nuclear factor κB, Rac-1/NADPH oxidase, and c-Jun kinase/c-Jun signaling cascades. Using a combination of adenoviruses encoding dominant-negative TAK1 and the TAK1 inhibitor 5Z-7-oxozeaenol, we demonstrated that the TRAF3-mediated activation of ischemic cascades was TAK1-dependent. More importantly, the adverse phenotypes observed in TRAF3-overexpressing mice were completely reversed when the TRAF3-TAK1 interaction was prevented. Therefore, we have shown that TRAF3 is a central regulator of ischemic pathways, including nuclear factor κB, Rac-1, and c-Jun kinase signaling, via its interaction with and activation of TAK1. Furthermore, certain components of the TRAF3-TAK1 signaling pathway are potentially promising therapeutic targets in ischemic stroke.

Oncostatin M Confers Neuroprotection against Ischemic Stroke.

Cell-surface receptors provide potential targets for the translation of bench-side findings into therapeutic strategies; however, this approach for the treatment of stroke is disappointing, at least partially due to an incomplete understanding of the targeted factors. Previous studies of oncostatin M (OSM), a member of the gp130 cytokine family, have been limited, as mouse models alone may not strongly resemble the human condition enough. In addition, the precise function of OSM in the CNS remains unclear. Here, we report that human OSM is neuroprotective in vivo and in vitro by recruiting OSMRß in the setting of ischemic stroke. Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMRß expression results in deteriorated stroke outcomes but that OSMRß overexpression in neurons is cerebroprotective. Moreover, administering recombinant human OSM to mice before the onset of I/R showed that human OSM can be protective in rodent models of ischemic stroke. Mechanistically, OSM/OSMRß activate the JAK2/STAT3 prosurvival signaling pathway. Collectively, these data support that human OSM may represent a promising drug candidate for stroke treatment. SIGNIFICANCE STATEMENT: OSM, a member of the gp130 cytokine family, regulates neuronal function and survival. OSM engages a second receptor, either LIFRα or OSMRß, before recruiting gp130. However, it is not clear whether OSM/OSMRß signaling is involved in neuroprotection in the setting of ischemic stroke. Recent studies show that, compared with mouse disease models, the OSM receptor system in rats more closely resembles that in humans. In the present study, we use genetic manipulations of OSMRß in both mouse and rat stroke models to demonstrate that OSMRß in neurons is critical for neuronal survival during cerebral ischemic/reperfusion. Interestingly, administration of human OSM also leads to improved stroke outcomes. Therefore, OSM may represent a promising drug candidate for stroke treatment.

A critical role for interferon regulatory factor 9 in cerebral ischemic stroke.

The failure of past efforts to develop effective stroke treatments is at least partially because these treatments often interfered with essential physiological functions, even though they are targeted toward pathophysiological events, such as inflammation, excitotoxicity, and oxidative stress. Thus, the direct targeting of endogenous neuroprotective or destructive elements holds promise as a potential new approach to treating this devastating condition. Interferon regulatory factor 9 (IRF9), a transcription factor that regulates innate immune responses, has been implicated in neurological pathology. Here, we provide new evidence that IRF9 directly mediates neuronal death in male mice. In response to ischemia/reperfusion (I/R), IRF9 accumulated in neurons. IRF9 deficiency markedly mitigated both poststroke neuronal death and neurological deficits, whereas the neuron-specific overexpression of IRF9 sensitized neurons to death. The histone deacetylase Sirt1 was identified as a novel negative transcriptional target of IRF9 both in vivo and in vitro. IRF9 inhibits Sirt1 deacetylase activity, culminating in the acetylation and activation of p53-mediated cell death signaling. Importantly, both the genetic and pharmacological manipulation of Sirt1 effectively counteracted the pathophysiological effects of IRF9 on stroke outcome. These findings indicate that, rather than activating a delayed innate immune response, IRF9 directly activates neuronal death signaling pathways through the downregulation of Sirt1 deacetylase in response to acute I/R stress.

Interferon regulatory factor 3 protects against adverse neo-intima formation.

AIMS: Vascular smooth muscle cell (VSMC) proliferation is central to the pathophysiology of neo-intima formation. Interferon regulatory factor 3 (IRF3) inhibits the growth of cancer cells and fibroblasts. However, the role of IRF3 in vascular neo-intima formation is unknown. We evaluated the protective role of IRF3 against neo-intima formation in mice and the underlying mechanisms. METHODS AND RESULTS: IRF3 expression was down-regulated in VSMCs after carotid wire injury in vivo, and in SMCs after platelet-derived growth factor (PDGF)-BB challenge in vitro. Global knockout of IRF3 (IRF3-KO) led to accelerated neo-intima formation and proliferation of VSMCs, whereas the opposite was seen in SMC-specific IRF3 transgenic mice. Mechanistically, we identified IRF3 as a novel regulator of peroxisome proliferator-activated receptor γ (PPARγ), a negative regulator of SMC proliferation after vascular injury. Binding of IRF3 to the AB domain of PPARγ in the nucleus of SMCs facilitated PPARγ transactivation, resulting in decreased proliferation cell nuclear antigen expression and suppressed proliferation. Overexpression of wild-type, but not truncated, IRF3 with a mutated IRF association domain (IAD) retained the ability to exert anti-proliferative effect. CONCLUSIONS: IRF3 inhibits VSMC proliferation and neo-intima formation after vascular injury through PPARγ activation.

TRAF1 is a critical regulator of cerebral ischaemia-reperfusion injury and neuronal death.

Stroke is a leading global cause of mortality and disability. Less than 5% of patients are able to receive tissue plasminogen activator thrombolysis within the necessary timeframe. Focusing on the process of neuronal apoptosis in the penumbra, which lasts from hours to days after ischaemia, appears to be promising. Here we report that tumour necrosis factor receptor-associated factor 1 (TRAF1) expression is markedly induced in wild-type mice 6 h after stroke onset. Using genetic approaches, we demonstrate that increased neuronal TRAF1 leads to elevated neuronal death and enlarged ischaemic lesions, whereas TRAF1 deficiency is neuroprotective. In addition, TRAF1-mediated neuroapoptosis correlates with the activation of the JNK pro-death pathway and inhibition of the Akt cell survival pathway. Finally, TRAF1 is found to exert pro-apoptotic effects via direct interaction with ASK1. Thus, ASK1 positively and negatively regulates the JNK and Akt signalling pathways, respectively. Targeting the TRAF1/ASK1 pathway may provide feasible therapies for stroke long after onset.