NLRC3 deficiency promotes hypoxia-induced pulmonary hypertension development via IKK/NF-κB p65/HIF-1α pathway.

Hypoxia-induced pulmonary hypertension is a subgroup of type 3 pulmonary hypertension (PH) with the recommended treatment limited to oxygen therapy and lacks potential therapeutic targets. To investigate the role of NLRC3 in hypoxia-induced PH and its potential mechanism, we first collected lung tissues of high-altitude pulmonary hypertension (HAPH) patients. Immunohistochemistry and immunofluorescence showed that NLRC3 was downregulated and was mainly co-localized with the smooth muscle cells of the pulmonary vessels in HAPH patients. Besides, we found that NLRC3 was also expressed in endothelial cells in HAPH patients for the first time. Then, wild type (WT) and NLRC3 knockout (NLRC3-/-) mice were used to construct hypoxia models and primary pulmonary arterial smooth muscle cells (PASMCs) of rats and endothelial cells were cultured for verification. Right heart catheterization and echocardiography suggested that NLRC3 knockout promoted right ventricular systolic pressure (RVSP) up-regulation, right ventricular hypertrophy and fibrosis in hypoxia-induced mice. This study first demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, Human umbilical vein endothelial cells (HUVECs) apoptosis, migration and inflammation through IKK/NF-κB p65/HIF-1α pathway in vitro and in vivo, further promoted vascular remodeling and PH progression, which provided a new target for the treatment of hypoxia-induced PH.

Thyroid-Disrupting Effects of Exposure to Fipronil and Its Metabolites from Drinking Water Based on Human Thyroid Follicular Epithelial Nthy-ori 3-1 Cell Lines.

Fipronil is a broad-spectrum insecticide used for plants and poultry. Owing to its widespread use, fipronil and its metabolites (fipronil sulfone, fipronil desulfinyl, and fipronil sulfide), termed FPM, can be frequently detected in drinking water and food. Fipronil can affect the thyroid function of animals, but the effects of FPM on the human thyroid remain unclear. We employed human thyroid follicular epithelial Nthy-ori 3-1 cells to examine combined cytotoxic responses, thyroid-related functional proteins including the sodium-iodide symporter (NIS), thyroid peroxidase (TPO), deiodinases I-III (DIO I-III), and the nuclear factor erythroid-derived factor 2-related factor 2 (NRF2) pathway induced by FPM of 1-1000-fold concentrations detected in school drinking water collected from a heavily contaminated area of the Huai River Basin. Thyroid-disrupting effects of FPM were evaluated by examining biomarkers of oxidative stress and thyroid function and tetraiodothyronine (T4) levels secreted by Nthy-ori 3-1 cells after FPM treatment. FPM activated the expression of NRF2, HO-1 (heme oxygenase 1), TPO, DIO I, and DIO II but inhibited NIS expression and increased the T4 level of thyrocytes, indicating that FPM can disrupt the function of human thyrocytes through oxidative pathways. Given the adverse impact of low FPM concentrations on human thyrocytes, supportive evidence from rodent studies, and the critical importance of thyroid hormones on development, the effects of FPM on the neurodevelopment and growth of children warrant priority attention.

High complement protein C1q levels in pulmonary fibrosis and non-small cell lung cancer associated with poor prognosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial pneumonia. Lung cancer, mainly non-small cell lung cancer (NSCLC), is a complication of idiopathic pulmonary fibrosis. IPF is also an independent risk factor of lung cancer. Some studies have shown that the complement system can promote the progression of interstitial pulmonary fibrosis. In addition, C1q has also demonstrated to exert a tumor-promoting effect in many tumors. However, the role of C1q in idiopathic pulmonary fibrosis and lung cancer still remain unclear. METHODS: We selected common differentially expressed genes in IPF and non-small cell lung cancer using datasets from GEO, and investigated common hub gene. The hub genes were validated in IPF by establishing mouse model of IPF and using another four datasets from the GEO. Multiple databases were analyzed including those of Kaplan-Meier Plotter, Tumor Immune Estimation Resource (TIMER2.0) and the Human Protein Atlas (HPA) for NSCLC. RESULTS: In this study, 37 common DEGs were identified in IPF and NSCLC including 32 up-regulated genes and 5 down-regulated genes, and C1q was identified as common hub gene. The methylation status of C1q decreased and the expression levels of C1q increased in both lung cancer and idiopathic pulmonary fibrosis. The prognosis of non-small cell lung cancer and IPF patients with high levels of C1q is poor. CONCLUSIONS: These results show that C1q participates in pulmonary fibrosis and non-small cell lung cancer, and may be a potential diagnostic / prognostic biomarker or a therapeutic target.

IL-17A secreted from lymphatic endothelial cells promotes tumorigenesis by upregulation of PD-L1 in hepatoma stem cells.

BACKGROUND & AIMS: The microenvironment regulates hepatoma stem cell behavior. However, the contributions of lymphatic endothelial cells to the hepatoma stem cell niche remain largely unknown; we aimed to analyze this contribution and elucidate the mechanisms behind it. METHODS: Associations between lymphatic endothelial cells and CD133+ hepatoma stem cells were analyzed by immunofluorescence and adhesion assays; with the effects of their association on IL-17A expression examined using western blot, quantitative reverse transcription PCR and luciferase reporter assay. The effects of IL-17A on the self-renewal and tumorigenesis of hepatoma stem cells were examined using sphere and tumor formation assays. The role of IL-17A in immune escape by hepatoma stem cells was examined using flow cytometry. The expression of IL-17A in hepatoma tissues was examined using immunohistochemistry. RESULTS: CD133+ hepatoma stem cells preferentially interact with lymphatic endothelial cells. The interaction between the mannose receptor and high-mannose type N-glycans mediates the interaction between CD133+ hepatoma stem cells and lymphatic endothelial cells. This interaction activates cytokine IL-17A expression in lymphatic endothelial cells. IL-17A promotes the self-renewal of hepatoma stem cells. It also promotes their immune escape, partly through upregulation of PD-L1. CONCLUSION: Interactions between lymphatic endothelial cells and hepatoma stem cells promote the self-renewal and immune escape of hepatoma stem cells, by activating IL-17A signaling. Thus, inhibiting IL-17A signaling may be a promising approach for hepatoma treatment. LAY SUMMARY: The microenvironment is crucial for the self-renewal and development of hepatoma stem cells, which lead to the development of liver cancer. Lymphatic endothelial cells are an important component of this niche microenvironment, helping hepatoma stem cells to self-renew and escape immune attack, by upregulating IL-17A signaling. Thus, targeting IL-17A signaling is a potential strategy for the treatment of hepatoma.

FNDC5/Irisin inhibits pathological cardiac hypertrophy.

Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown in vitro Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.

NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.

NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has important roles in inflammation and innate immunity. NLRC5 was highly expressed in kidney from streptozotocin-induced diabetic mice, db/ db mice and patients with diabetes. Based on that evidence, the present study was designed to explore the roles of NLRC5 in the progression of diabetic nephropathy (DN). We examined kidney injury, including inflammation and fibrosis in Nlrc5 gene knockout ( Nlrc5-/-) and wild-type (WT) diabetic mice. We found that Nlrc5-/- mice developed less-severe diabetic kidney injury compared with WT mice, exhibiting lower albuminuria, less fibronectin and collagen IV expression, and reduced macrophage infiltration but greater levels of podocin and nephrin in the diabetic kidney. The underlying mechanisms were further investigated in vitro with peritoneal macrophages and mesangial cells treated with high glucose. Reduced proinflammatory effect was observed in peritoneal macrophages from Nlrc5-/- mice, associated with NF-κB pathway suppression. Knocking down of NLRC5 in mesangial cells in high-glucose conditions was also associated with reduced NF-κB and TGF-ß/Smad signaling. Taken together, NLRC5 promotes inflammation and fibrosis during DN progression partly through the effects on NF-κB and TGF-ß/Smad pathways. NLRC5 may, therefore, be a promising therapeutic target for DN treatment.-Luan, P., Zhuang, J., Zou, J., Li, H., Shuai, P., Xu, X., Zhao, Y., Kou, W., Ji, S., Peng, A., Xu, Y., Su, Q., Jian, W., Peng, W. NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.

The inhibition of the effect and mechanism of vascular intimal hyperplasia in Tiam1 knockout mice.

T-Cell Lymphoma Invasion and Metastasis 1 (Tiam1) is a specific nucleotide exchange factor (GEF) that can activate Rho-like GTPase and Rac1 and regulate various cellular processes, including cell cycle progression and cell migration. The roles of Tiam1 in vascular intimal hyperplasia, especially in vascular smooth muscle cell proliferation and migration, are not fully understood. In this study, we investigated the effect of Tiam1 on vascular intimal hyperplasia in a carotid artery ligation model and human aortic smooth muscle cells (HASMCs). We found that the expression of Tiam1 was up-regulated in the neointima of carotid artery ligation mice and that Tiam1-/- mice following carotid artery ligation had less neointimal formation compared with wild type mice. Knockdown of Tiam1 by siRNA markedly attenuated PDGF-induced migration and proliferation in HASMCs by inhibiting the activation of Rac1. Therefore, these results suggest that Tiam1 is an important regulator of intima hyperplasia. It may regulate vascular intimal hyperplasia through the activation of Rac1.

The Yin-Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling.

OBJECTIVE: DNA methylation plays an important role in chronic diseases such as atherosclerosis, yet the mechanisms are poorly understood. The objective of our study is to indicate the regulatory mechanisms of DNA methylation in vascular smooth muscle cells (VSMCs) and its roles in atherosclerosis. APPROACH AND RESULTS: In ApoE-/- mice fed a Western diet, DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, significantly attenuated atherosclerotic lesions (20.1±2.2% versus 30.8±7.5%; P=0.016) and suppressed DNA methyltransferase activity and concomitantly decreased global 5-methylcytosine content in atherosclerotic lesions of ApoE-/- mice. Using a carotid ligation model, we found that 5-aza-2'-deoxycytidine also dramatically inhibited neointimal formation (intimal area: 2.25±0.14×104 versus 4.07±0.22×104 µm2; P<0.01). Abnormal methylation status at the promoter of ten-eleven translocation 2, one of the key demethylation enzymes in mammals, was ameliorated after 5-aza-2'-deoxycytidine treatment, which in turn caused an increase in global DNA hydroxymethylation and 5-hydroxymethylcytosine enrichment at the promoter of Myocardin. In vitro, 5-aza-2'-deoxycytidine treatment or DNA methyltransferase 1 knockdown decreased global 5-methylcytosine content and restored Myocardin expression in VSMCs induced by platelet-derived growth factor, thus preventing excessive VSMCs dedifferentiation, proliferation, and migration. Furthermore, DNA methyltransferase 1 binds to ten-eleven translocation 2 promoter and is required for ten-eleven translocation 2 methylation in VSMCs. CONCLUSIONS: The inhibitory effects of DNA demethylation on global 5-methylcytosine content and ten-eleven translocation 2 hypermethylation in atherosclerotic aorta can recover 5-hydroxymethylcytosine enrichment at the Myocardin promoter and prevent VSMC dedifferentiation and vascular remodeling.

Association of the single nucleotide polymorphism in chromosome 9p21 and chromosome 9q33 with coronary artery disease in Chinese population.

BACKGROUND: Our study aims to explore the association of rs7025486 single-nucleotide polymorphisms (SNP) in DAB2IP and rs1333049 on chromosome 9p21.3 with the coronary artery disease in Chinese population. METHODS: All patients came from the east China area and underwent coronary angiography. Rs7025486 and rs1333049 polymorphism were genotyped in 555 patients with CAD and in 480 healthy controls that underwent coronary angiography. RESULTS: In Chinese population, the rs7025486 genotype in the case group was no significant different than the control group (P = 0.531).Meanwhile, the rs1333049 SNP has statistically significant (P = 0.006), which was the independent risk factors for CAD (OR1.252, P = 0.039), and consistent with the past studies conclusion. CONCLUSION: Genotype of rs1333049 on chromosome 9p21, but not rs7025486 on chromosome 9q33, is an independent determinant of the incidence of CAD in Chinese population.

Comparison of circulating dendritic cell and monocyte subsets at different stages of atherosclerosis: insights from optical coherence tomography.

BACKGROUND: While specific patterns of circulating dendritic cells (DCs) and monocytes are associated with the incidence of coronary artery disease, the characterization of circulating DC and monocyte subsets in patients with different stages of atherosclerosis remains unclear. METHODS: Forty-eight patients with unstable angina pectoris (UAP) diagnosed by angiography were enrolled. Likewise, 31 patients with ST-segment elevation myocardial infarction (STEMI) were enrolled and confirmed with the presence of thrombosis by angiography. Plaque features of 48 UAP patients were evaluated at the culprit lesions by OCT. Circulating myeloid DCs (mDCs), plasmacytoid DCs (pDCs) and monocyte subsets were analyzed using flow cytometry. RESULTS: The proportions and absolute counts of mDC2s, which specifically express CD141 and possess the ability to activate CD8+ T lymphocytes, significantly decreased in patients with UAP and STEMI when compared with controls (0.08 × 104 ± 0.05 × 104/ml and 0.08 × 104 ± 0.06 × 104/ml vs. 0.11 × 104 ± 0.06 × 104/ml, p = 0.027). On the other hand, patients with UAP and STEMI had significantly higher proportions and counts of Mon2 subsets. In the OCT subgroup, patients with thin-cap fibroatheroma (TCFA) had higher proportions and absolute number of Mon2 (11.96% ± 4.27% vs. 9.42% ± 4.05%, p = 0.034; 5.17 × 104/ml ± 1.92 × 104/ml vs. 3.53 × 104/ml ± 2.65 × 104/ml, p = 0.045) than those without TCFA. However, there was no remarkable difference in mDC2s between patients with and without TCFA. CONCLUSIONS: Circulating Mon2 appears to be a promising marker for the severity of atherosclerotic plaque.

Role of p38 MAPK activation and mitochondrial cytochrome-c release in allicin-induced apoptosis in SK-N-SH cells.

Here, we investigate the apoptotic effect of allicin, the predominant component of freshly crushed garlic, on neuroblastoma cells. In this paper, the authors have first assessed the effect of allicin on human neuroblastoma SK-N-SH cells and then investigated the underlying mechanism. The results indicate that allicin suppresses SK-N-SH cell growth in a dose-dependent and time-dependent manner and that 5 µmol/l of allicin leads to a significant increase in apoptotic rate with annexin-V/PI double staining. Western blot analysis shows that treatment with allicin-induced apoptosis through activation of caspases-3 and 9. Phosphorylation of p38 MAPK contributes to allicin-induced apoptosis upstream of caspase activation. Using p38 MAPK inhibitor, the authors discovered that p38 MAPK activation subsequently induces the release of cytochrome-c from mitochondria into the cytosol. Taken together, the results demonstrate that allicin can activate the p38 MAPK pathway, which leads to mitochondrial release of cytochrome-c, thus inducing SK-N-SH cell apoptosis. Overall, this study suggests that allicin may be used as one of the novel pharmacological treatment strategies in neuroblastoma.

XAV939 Inhibits Intima Formation by Decreasing Vascular Smooth Muscle Cell Proliferation and Migration Through Blocking Wnt Signaling.

BACKGROUND: Excessive proliferation, migration, and oxidative stress of vascular smooth muscle cells (VSMCs) are key mechanisms involved in intima formation, which is the basic pathological process of in stent restenosis. This study aims at exploring the role of XAV939 in proliferation, migration, and reactive oxygen species (ROS) generation of VSMCs, and hence evaluating its effects on intima formation. METHODS: Carotid artery ligation models for C57BL/6 mice were established and gave them different intervention: saline, XAV939, Axin2 overexpression adenovirus, and negative control adenovirus. The intima formation was assayed by intima area and intima/media ratio. To investigate the underlying mechanisms, primary rat VSMCs were cultured and treated with XAV939 and platelet-derived growth factor-BB. EdU, direct cell counting, cell wound-healing assay, and flow cytometry were used to measure proliferation, migration, cell cycle, apoptosis, and ROS generation of VSMCs, respectively. By Western blot, we examined proliferating cell nuclear antigen, Cyclin D1, Cyclin E, p21, ß-actin, JNK, phosphorylated JNK, Axin2 and ß-catenin expression. Immunofluorescence staining and confocal microscopy were conducted to detect translocation of ß-catenin. RESULTS: XAV939 inhibited intima formation, which was exhibited by the loss of intima area and I/M ratio and attenuated proliferation, migration, and ROS generation, as well as promoted cell cycle arrest of VSMCs. Specifically, XAV939 inhibited Wnt pathway. CONCLUSIONS: XAV939 attenuates intima formation because of its inhibition of proliferation, migration, and apoptosis of VSMCs through suppression of Wnt signaling pathway.

Endothelial TET2 regulates the white adipose browning and metabolism via fatty acid oxidation in obesity.

Obesity is a complex metabolic disorder, manifesting as excessive accumulation of body fat. Ten-Eleven Translocation-2 (TET2) has garnered significant attention in the context of obesity due to its crucial role in epigenetic regulation and metabolic homeostasis. In this study, we aimed to investigate the effect of endothelial TET2 on obesity and explore the potential mechanism. We generated endothelial cell-specific TET2 deficiency mice and investigated endothelial TET2 using transcriptomic and epigenomic analyses. We determined the downregulation of endothelial TET2 in white adipose tissues. Furthermore, we identified that endothelial TET2 loss aggravated high-fat diet-induced obesity by inhibiting vascularization and thus suppressing white adipose tissue browning. Mechanistically, endothelial TET2 modulates obesity by engaging in endothelial fatty acid oxidation and angiocrine-mediated secretion of bone morphogenetic protein 4 (BMP4), in which nuclear factor-erythroid 2-related factor 2 (NRF2) serves as a key mediator. Our study reveals that endothelial TET2 regulates white adipose tissue browning by interacting with NRF2 to facilitate fatty acid oxidation and lipolysis in adipocytes.

TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53.

Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC-MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD+ transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2+ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.

Sex Differences in Coronary Inflammation and Atherosclerosis Phenotypes in Response to Imaging Marker of Stress-Related Neural Activity.

BACKGROUND: Sex-specific differences in coronary phenotypes in response to stress have not been elucidated. This study investigated the sex-specific differences in the coronary computed tomography angiography-assessed coronary response to mental stress. METHODS: This retrospective study included patients with coronary artery disease and without cancer who underwent resting 18F-fluorodexoyglucose positron emission tomography/computed tomography and coronary computed tomography angiography within 3 months. 18F-flourodeoxyglucose resting amygdalar uptake, an imaging biomarker of stress-related neural activity, coronary inflammation (fat attenuation index), and high-risk plaque characteristics were assessed by coronary computed tomography angiography. Their correlation and prognostic values were assessed according to sex. RESULTS: A total of 364 participants (27.7% women and 72.3% men) were enrolled. Among those with heightened stress-related neural activity, women were more likely to have a higher fat attenuation index (43.0% versus 24.0%; P=0.004), while men had a higher frequency of high-risk plaques (53.7% versus 39.3%; P=0.036). High amygdalar 18F-flourodeoxyglucose uptake (B-coefficient [SE], 3.62 [0.21]; P<0.001) was selected as the strongest predictor of fat attenuation index in a fully adjusted linear regression model in women, and the first-order interaction term consisting of sex and stress-related neural activity was significant (P<0.001). Those with enhanced imaging biomarkers of stress-related neural activity showed increased risk of major adverse cardiovascular event both in women (24.5% versus 5.1%; adjusted hazard ratio, 3.62 [95% CI, 1.14-17.14]; P=0.039) and men (17.2% versus 6.9%; adjusted hazard ratio, 2.72 [95% CI, 1.10-6.69]; P=0.030). CONCLUSIONS: Imaging-assessed stress-related neural activity carried prognostic values irrespective of sex; however, a sex-specific mechanism linking psychological stress to coronary plaque phenotypes existed in the current hypothesis-generating study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05545618.

Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes.

BACKGROUND: Ischemic diseases represent a major global health care burden. Angiogenesis is critical in recovery of blood flow and repair of injured tissue in ischemic diseases. Ten-eleven translocation protein 2 (TET2), a member of DNA demethylases, is involved in many pathological processes. However, the role of TET2 in angiogenesis is still unrevealed. METHODS: TET2 was screened out from three DNA demethylases involved in 5-hydroxylmethylcytosine (5-hmC) regulation, including TET1, TET2 and TET3. Knockdown by small interfering RNAs and overexpression by adenovirus were used to evaluate the role of TET2 on the function of endothelial cells. The blood flow recovery and density of capillary were analyzed in the endothelial cells-specific TET2-deficient mice. RNA sequencing was used to identify the TET2-mediated mechanisms under hypoxia. Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation-qPCR (ChIP-qPCR) and glucosylated hydroxymethyl-sensitive-qPCR (GluMS-qPCR) were further performed to reveal the interaction of TET2 and STAT3. RESULTS: TET2 was significantly downregulated in endothelial cells under hypoxia and led to a global decrease of 5-hmC level. TET2 knockdown aggravated the hypoxia-induced dysfunction of endothelial cells, while TET2 overexpression alleviated the hypoxia-induced dysfunction. Meanwhile, the deficiency of TET2 in endothelial cells impaired blood flow recovery and the density of capillary in the mouse model of hindlimb ischemia. Mechanistically, RNA sequencing indicated that the STAT3 signaling pathway was significantly inhibited by TET2 knockdown. Additionally, Co-IP, ChIP-qPCR and GluMS-qPCR further illustrated that STAT3 recruited and physically interacted with TET2 to activate STAT3 target genes. As expected, the effects of TET2 overexpression were completely suppressed by STAT3 silencing in vitro. CONCLUSIONS: Our study suggests that the deficiency of TET2 in endothelial cells impairs angiogenesis via suppression of the STAT3 signaling pathway. These findings give solid evidence for TET2 to be a therapeutic alternative for ischemic diseases.

Immature neutrophil is associated with coronary plaque vulnerability based on optical coherence tomography analysis.

INTRODUCTION: High neutrophil to lymphocyte ratio is considered to predict poor prognosis of acute coronary syndrome (ACS). However, the association of neutrophil subpopulation with plaque vulnerability and the incidence of ACS remains unknown. METHODS AND RESULTS: Blood samples from 48 patients with unstable angina (UA), 31 with ST-segment elevation myocardial infarction (STEMI) and 33 healthy controls were collected at admission. The morphology of coronary plaques in 48 UA patients were further evaluated by optical coherence tomography (OCT). According to maturation stages of neutrophils and the expression of CD10 and CD101, circulating neutrophils could be divided into pre-neutrophils (CD101-CD10-), immature neutrophils (CD101+CD10-) and mature neutrophils (CD101+CD10+). While the number of pre-neutrophil was quite low in blood and comparable among three groups, the absolute counts and percentage of CD10- immature neutrophils were higher in peripheral bloods of UA and STEMI patients compared with those in healthy controls. The concentration of plasma myeloperoxidase was positively associated with the percentage of CD10- immature neutrophils. Furthermore, UA patients with thin-cap fibroatheroma (TCFA) observed by OCT had a higher proportion and larger number of immature neutrophils as compared to those without TCFA. The percentage of immature neutrophils also closely correlated with plaque rupture and the feature of vulnerable plaque, including thinner fibrous cap and larger lipid core, but did not associate with percent lumen stenosis. CONCLUSION: Our findings emphasize that the abnormally increased level of CD10- immature neutrophils may sever as a promising marker of the incidence of ACS and plaque vulnerability.

A novel clinical prediction scoring system of high-altitude pulmonary hypertension.

Background: High-altitude pulmonary hypertension (HAPH) is a common disease in regions of high altitude where performing right heart catheterization (RHC) is challenging. The development of a diagnostic scoring system is crucial for effective disease screening. Methods: A total of 148 individuals were included in a retrospective analysis, and an additional 42 residents were prospectively enrolled. We conducted a multivariable analysis to identify independent predictors of HAPH. Subsequently, we devised a prediction score based on the retrospective training set to anticipate the occurrence and severity of HAPH. This scoring system was further subjected to validation in the prospective cohort, in which all participants underwent RHC. Results: This scoring system, referred to as the GENTH score model (Glycated hemoglobin [OR = 4.5], Echocardiography sign [OR = 9.1], New York Heart Association-functional class [OR = 12.5], Total bilirubin [OR = 3.3], and Hematocrit [OR = 3.6]), incorporated five independent risk factors and demonstrated strong predictive accuracy. In the training set, the area under the curve (AUC) values for predicting the occurrence and severity of HAPH were 0.851 and 0.832, respectively, while in the validation set, they were 0.841 and 0.893. In the validation set, GENTH score model cutoff values of ≤18 or >18 points were established for excluding or confirming HAPH, and a threshold of >30 points indicated severe HAPH. Conclusions: The GENTH score model, combining laboratory and echocardiography indicators, represents an effective tool for distinguishing potential HAPH patients and identifying those with severe HAPH. This scoring system improves the clinical screening of HAPH diseases and offers valuable insights into disease diagnosis and management.

Macrophage-Specific NLRC5 Protects From Cardiac Remodeling Through Interaction With HSPA8.

Macrophages regulate inflammation and the process of tissue repair. Therefore, a better understanding of macrophages in the pathogenesis of heart failure is needed. In patients with hypertrophic cardiomyopathy, NLRC5 was significantly increased in circulating monocytes and cardiac macrophages. Myeloid-specific deletion of NLRC5 aggravated pressure overload-induced pathological cardiac remodeling and inflammation. Mechanistically, NLRC5 interacted with HSPA8 and suppressed NF-κB pathway in macrophages. The absence of NLRC5 in macrophages promoted the secretion of cytokines such as interleukin-6 (IL-6), which affected cardiomyocyte hypertrophy and cardiac fibroblast activation. Tocilizumab, an anti-IL-6 receptor antagonist, may be a novel therapeutic strategy for cardiac remodeling and chronic heart failure.

Stress-Related Neural Activity Associates With Coronary Plaque Vulnerability and Subsequent Cardiovascular Events.

BACKGROUND: Stress-related neural activity (SNA) assessed by amygdalar activity can predict cardiovascular events. However, its mechanistic linkage with plaque vulnerability is not fully elucidated. OBJECTIVES: The authors aimed to investigate the association of SNA with coronary plaque morphologic and inflammatory features as well as their ability in predicting major adverse cardiovascular events (MACE). METHODS: A total of 299 patients with coronary artery disease (CAD) and without cancer underwent 18F-fluorodexoyglucose positron emission tomography/computed tomography (PET/CT) and available coronary computed tomographic angiography (CCTA) between January 1, 2013, and December 31, 2020. SNA and bone-marrow activity (BMA) were assessed with validated methods. Coronary inflammation (fat attenuation index [FAI]) and high-risk plaque (HRP) characteristics were assessed by CCTA. Relations between these features were analyzed. Relations between SNA and MACE were assessed with Cox models, log-rank tests, and mediation (path) analyses. RESULTS: SNA was significant correlated with BMA (r = 0.39; P < 0.001) and FAI (r = 0.49; P < 0.001). Patients with heightened SNA are more likely to have HRP (40.7% vs 23.5%; P = 0.002) and increase risk of MACE (17.2% vs 5.1%, adjusted HR 3.22; 95% CI: 1.31-7.93; P = 0.011). Mediation analysis suggested that higher SNA associates with MACE via a serial mechanism involving BMA, FAI, and HRP. CONCLUSIONS: SNA is significantly correlated with FAI and HRP in patients with CAD. Furthermore, such neural activity was associated with MACE, which was mediated in part by leukopoietic activity in the bone marrow, coronary inflammation, and plaque vulnerability.