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Abstract Background Diabetic macroangiopathy has been the main cause of death and disability in diabetic patients. The mechanisms underlying smooth muscle cell transformation and metabolic reprogramming other than abnormal glucose and lipid metabolism remain to be further explored. Method Single-cell transcriptome, spatial transcriptome and spatial metabolome sequencing were performed on anterior tibial artery from 11 diabetic patients with amputation. Multi-omics integration, cell communication analysis, time series analysis, network analysis, enrichment analysis, and gene expression analysis were performed to elucidate the potential molecular features. Result We constructed a spatial multiomics map of diabetic blood vessels based on multiomics integration, indicating single-cell and spatial landscape of transcriptome and spatial landscape of metabolome. At the same time, the characteristics of cell composition and biological function of calcified regions were obtained by integrating spatial omics and single cell omics. On this basis, our study provides favorable evidence for the cellular fate of smooth muscle cells, which can be transformed into pro-inflammatory chemotactic smooth muscle cells, macrophage-like smooth muscle cells/foam-like smooth muscle cells, and fibroblast/chondroblast smooth muscle cells in the anterior tibial artery of diabetic patients. The smooth muscle cell phenotypic transformation is driven by transcription factors net including KDM5B, DDIT3, etc. In addition, in order to focus on metabolic reprogramming apart from abnormal glucose and lipid metabolism, we constructed a metabolic network of diabetic vascular activation, and found that HNMT and CYP27A1 participate in diabetic vascular metabolic reprogramming by combining public data. Conclusion This study constructs the spatial gene-metabolism map of the whole anterior tibial artery for the first time and reveals the characteristics of vascular calcification, the phenotypic transformation trend of SMCs, and the transcriptional driving network of SMCs phenotypic transformation of diabetic macrovascular disease. In the perspective of combining the transcriptome and metabolome, the study demonstrates the activated metabolic pathways in diabetic blood vessels and the key genes involved in diabetic metabolic reprogramming. Graphical abstract

Abstract Background Although the Healthy Eating Index (HEI) is widely recommended to reduce the risk of cardiovascular disease and all-cause death, there are significant differences in physiological and nutritional factors between the sexes. The potential impact of sex on adult dietary health is still poorly understood. The study was designed to assess whether the health benefits of diet differed by sex. Methods In a prospective study of 39,567 U.S. adults (51.2% female, age 46.8 ± 17.6 years), we examined sex-specific, multivariable-adjusted associations of HEI with all-cause mortality and cardiovascular disease mortality. Restricted cubic splines (RCS), subgroup analysis, propensity score matching (PSM), random forest feature importance, and sensitivity analysis were also used. Results During 328,403 person-years of follow-up, a total of 4754 all-cause deaths were recorded, including 1481 cardiovascular deaths. Compared to the lowest quartile of HEI, the all-cause mortality rate of females and males in the highest quartile array decreased by 34% (HR 0.66 [95% CI 0.55–0.8]) and 15% (HR 0.85 [95% CI 0.73–0.99]), respectively. The restricted cubic spline showed a linear inverse association between baseline HEI and all-cause mortality and CVD mortality, with similar sex-specific results. Similarly, component scores were sex-specific for mortality risk, with females benefiting more from diet. The benefits of dairy products, vegetables, and sodium scores on the risk of all-cause death were higher in males and females. However, the benefits of vegetable, sodium, and fatty acid scores on the risk of cardiovascular death were different. Conclusions In the adult population of the U.S., there are more opportunities for females to reduce the risk of all-cause mortality and cardiovascular mortality from the same dose of healthy dietary intake than males. These findings could reduce the risk of death by motivating the population, especially females, to consume healthy dietary components, especially vegetables and dairy products.

Abstract Background Dyslipidemia and abnormal cholesterol metabolism are closely related to coronary artery calcification (CAC) and are also critical factors in cardiovascular disease death. In recent years, the atherogenic index of plasma (AIP) has been widely used to evaluate vascular sclerosis. This study aimed to investigate the potential association of AIP between CAC and major adverse cardiovascular events (MACEs). Methods This study included 1,121 participants whose CACs were measured by multislice spiral CT. Participants’ CAC Agatston score, CAC mass, CAC volume, and number of vessels with CACs were assessed. AIP is defined as the base 10 logarithm of the ratio of triglyceride (TG) concentration to high-density lipoprotein-cholesterol (HDL-C) concentration. We investigated the multivariate-adjusted associations between AIP, CAC, and MACEs. The mediating role of the AIP in CAC and MACEs was subsequently discussed. Results During a median follow-up of 31 months, 74 MACEs were identified. For each additional unit of log-converted CAC, the MACE risk increased by 48% (HR 1.48 [95% CI 1.32–1.65]). For each additional unit of the AIP (multiplied by 10), the MACEs risk increased by 19%. Causal mediation analysis revealed that the AIP played a partial mediating role between CAC (CAC Agatston score, CAC mass) and MACEs, and the mediating proportions were 8.16% and 16.5%, respectively. However, the mediating effect of CAC volume tended to be nonsignificant (P = 0.137). Conclusions An increased AIP can be a risk factor for CAC and MACEs. Biomarkers based on lipid ratios are a readily available and low-cost strategy for identifying MACEs and mediating the association between CAC and MACEs. These findings provide a new perspective on CAC treatment, early diagnosis, and prevention of MACEs.

Abstract Backgroud The association between caffeine intake and mortality in prediabetes and diabetes is not well defined. This study was designed to investigate the association between caffeine intake and all-cause mortality and cardiovascular disease (CVD) mortality in adults with prediabetes and diabetes in the United States. Methods This analysis included 18,914 adult patients with diabetes and prediabetes from the National Health and Nutrition Examination Survey (NHANES) 2003–2018. Follow-up extended to December 31, 2019. Weighted Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality and CVD mortality. Results During 142,460 person-years of follow-up, there were 3,166 cases of all-cause mortality and 1,031 cases of CVD mortality recorded. In the fully adjusted models, caffeine intake showed a significant dose-response association with the risk of all-cause mortality and CVD mortality in individuals with diabetes and prediabetes. When comparing extreme quartiles of caffeine intake, the multivariable-adjusted hazard ratio for all-cause mortality was 0.78 (0.67–0.91) (P for trend = 0.007); however, there was no significant association with the risk of CVD mortality. Results remained consistent in stratified analyses by sex, age, race/ethnicity, education level, family income-poverty ratio, BMI, hypertension, smoking status, alcohol intake, and HEI-2015. Conclusions This study suggests that caffeine intake is significantly inversely associated with the risk of all-cause mortality in individuals with diabetes and prediabetes. In individuals with prediabetes, there is also a significant inverse association between caffeine intake and CVD events, but this association is not present in those with diabetes. Graphical Abstract

Atherosclerosis is a chronic inflammatory disease characterised by plaque accumulation in the arteries. Macrophages are immune cells that are crucial in the development of atherosclerosis. Macrophages can adopt different phenotypes, with the M1 phenotype promoting inflammation while the M2 phenotype counteracting it. This review focuses on the factors that drive the polarisation of M1 macrophages towards a pro-inflammatory phenotype during AS. Additionally, we explored metabolic reprogramming mechanisms and cytokines secretion by M1 macrophages. Hyperlipidaemia is widely recognised as a major risk factor for atherosclerosis. Modified lipoproteins released in the presence of hyperlipidaemia can trigger the release of cytokines and recruit circulating monocytes, which adhere to the damaged endothelium and differentiate into macrophages. Macrophages engulf lipids, leading to the formation of foam cells. As atherosclerosis progresses, foam cells become the necrotic core within the atherosclerotic plaques, destabilising them and triggering ischaemic disease. Furthermore, we discuss recent research focusing on targeting macrophages or inflammatory pathways for preventive or therapeutic purposes. These include statins, PCSK9 inhibitors, and promising nanotargeted drugs. These new developments hold the potential for the prevention and treatment of atherosclerosis and its related complications.

Vascular calcification (VC) is active and regulates extraosseous ossification progress, which is an independent predictor of cardiovascular disease (CVD) morbidity and mortality. Endothelial cells (ECs) line the innermost layer of blood vessels and directly respond to changes in flow shear stress and blood composition. Together with vascular smooth muscle cells, ECs maintain vascular homeostasis. Increased evidence shows that ECs have irreplaceable roles in VC due to their high plasticity. Endothelial progenitor cells, oxidative stress, inflammation, autocrine and paracrine functions, mechanotransduction, endothelial-to-mesenchymal transition (EndMT), and other factors prompt ECs to participate in VC. EndMT is a dedifferentiation process by which ECs lose their cell lineage and acquire other cell lineages; this progress coexists in both embryonic development and CVD. EndMT is regulated by several signaling molecules and transcription factors and ultimately mediates VC via osteogenic differentiation. The specific molecular mechanism of EndMT remains unclear. Can EndMT be reversed to treat VC? To address this and other questions, this study reviews the pathogenesis and research progress of VC, expounds the role of ECs in VC, and focuses on the regulatory factors underlying EndMT, with a view to providing new concepts for VC prevention and treatment.

At present, the global incidence of diabetes has increased in countries with large populations, and the changes in developing regions are particularly worthy of attention. In the past 40 years or so, the income situation in China, India, and other countries has exploded, leading to changes in the way of life and work as well as an increase in the prevalence of diabetes. Metabolic disorders caused by diabetes can lead to secondary vascular complications, which have long-term malignant effects on the heart, kidneys, brain, and other vital organs of patients. Adequate primary prevention measures are needed to reduce the incidence of diabetic vascular complications, and more attention should be given to treatment after the disease. To this end, it is necessary to determine a standardized drug and physical therapy system and to build a more efficient and low-cost chronic disease management system.

Diabetes is a complex metabolic disease characterized by hyperglycemia. Its complications are various, often involving the heart, brain, kidney, and other essential organs. At present, the number of diabetic patients in the world is growing day by day. The cardiovascular disease caused by diabetes has dramatically affected the quality of life of diabetic patients. It is the leading cause of death of diabetic patients. Diabetic patients often suffer from microvascular angina pectoris without obstructive coronary artery disease. Still, there are typical ECG ischemia and angina pectoris, that is, chest pain and dyspnea under exercise. Unlike obstructive coronary diseases, nitrate does not affect chest pain caused by coronary microvascular angina in most cases. With the increasing emphasis on diabetic microvascular angina, the need for accurate diagnosis of the disease is also increasing. We can use SPECT, PET, CMR, MCE, and other methods to evaluate coronary microvascular function. SPECT is commonly used in clinical practice, and PET is considered the gold standard for non-invasive detection of myocardial blood flow. This article mainly introduces the research progress of these imaging methods in detecting microvascular angina in diabetic patients.

Atherosclerosis is a multifaceted disease characterized by the formation and accumulation of plaques that attach to arteries and cause cardiovascular disease and vascular embolism. A range of diagnostic techniques, including selective coronary angiography, stress tests, computerized tomography, and nuclear scans, assess cardiovascular disease risk and treatment targets. However, there is currently no simple blood biochemical index or biological target for the diagnosis of atherosclerosis. Therefore, it is of interest to find a biochemical blood marker for atherosclerosis. Three datasets from the Gene Expression Omnibus (GEO) database were analyzed to obtain differentially expressed genes (DEG) and the results were integrated using the Robustrankaggreg algorithm. The genes considered more critical by the Robustrankaggreg algorithm were put into their own data set and the data set system with cell classification information for verification. Twenty-one possible genes were screened out. Interestingly, we found a good correlation between RPS4Y1 , EIF1AY , and XIST . In addition, we know the general expression of these genes in different cell types and whole blood cells. In this study, we identified BTNL8 and BLNK as having good clinical significance. These results will contribute to the analysis of the underlying genes involved in the progression of atherosclerosis and provide insights for the discovery of new diagnostic and evaluation methods.

Vascular calcification, a common pathological phenomenon in atherosclerosis, diabetes, hypertension, and other diseases, increases the incidence and mortality of cardiovascular diseases. Therefore, the prevention and detection of vascular calcification play an important role. At present, various techniques have been applied to the analysis of vascular calcification, but clinical examination mainly depends on non-invasive and invasive imaging methods to detect and quantify. Computed tomography (CT), as a commonly used clinical examination method, can analyze vascular calcification. In recent years, with the development of technology, in addition to traditional CT, some emerging types of CT, such as dual-energy CT and micro CT, have emerged for vascular imaging and providing anatomical information for calcification. This review focuses on the latest application of various CT techniques in vascular calcification.

Cardiovascular diseases (CVDs) are major causes of mortality and morbidity in the modern society. The rupture of atherosclerotic plaque can induce thrombus formation, which is the main cause of acute cardiovascular events. Recently, many studies have demonstrated that there are some relationships between microbiota and atherosclerosis. In this review, we will focus on the effect of the microbiota and the microbe-derived metabolites, including trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and lipopolysaccharide (LPS), on the stability of atherosclerotic plaque. Finally, we will conclude with some therapies based on the microbiota and its metabolites.

Phosphatidylinositol 3 kinase (PI3K) is a key molecule in the initiation of signal transduction pathways after the binding of extracellular signals to cell surface receptors. An intracellular kinase, PI3K activates multiple intracellular signaling pathways that affect cell growth, proliferation, migration, secretion, differentiation, transcription and translation. Dysregulation of PI3K activity, and as aberrant PI3K signaling, lead to a broad range of human diseases, such as cancer, immune disorders, diabetes, and cardiovascular diseases. A growing number of studies have shown that PI3K and its signaling pathways play key roles in the pathophysiological process of atherosclerosis. Furthermore, drugs targeting PI3K and its related signaling pathways are promising treatments for atherosclerosis. Therefore, we have reviewed how PI3K, an important regulatory factor, mediates the development of atherosclerosis and how targeting PI3K can be used to prevent and treat atherosclerosis.

Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.

Vascular calcification is a high incidence and high risk disease with increasing morbidity and high mortality, which is considered the consequence of smooth muscle cell transdifferentiation initiating the mechanism of accumulation of hydroxyl calcium phosphate. Vascular calcification is also thought to be strongly associated with poor outcomes in diabetes and chronic kidney disease. Numerous studies have been accomplished; however, the specific mechanism of the disease remains unclear. Development of the genome project enhanced the understanding of life science and has entered the post-genomic era resulting in a variety of omics techniques used in studies and a large amount of available data; thus, a new perspective on data analysis has been revealed. Omics has a broader perspective and is thus advantageous over a single pathway analysis in the study of complex vascular calcification mechanisms. This paper reviews in detail various omics studies including genomics, proteomics, transcriptomics, metabolomics and multiple group studies on vascular calcification. Advances and deficiencies in the use of omics to study vascular calcification are presented in a comprehensive view. We also review the methodology of the omics studies and omics data analysis and processing. In addition, the methodology and data processing presented here can be applied to other areas. An omics landscape perspective across the boundaries between genomics, transcriptomics, proteomics and metabolomics is used to examine the mechanisms of vascular calcification. The perspective combined with various technologies also provides a direction for the subsequent exploration of clinical significance.

Vascular calcification is the transformation of arterial wall mesenchymal cells, particularly smooth muscle cells (SMCs), into osteoblast phenotypes by various pathological factors. Additionally, vascular transformation mediates the abnormal deposition of calcium salts in the vascular wall, such as intimal and media calcification. Various pathological types have been described, such as calcification and valve calcification. The incidence of vascular calcification in patients with diabetes is much higher than that in nondiabetic patients, representing a critical cause of cardiovascular events in patients with diabetes. Because basic research on the clinical transformation of vascular calcification has yet to be conducted, this study systematically expounds on the risk factors for vascular calcification, vascular bed differences, sex differences, ethnic differences, diagnosis, severity assessments, and treatments to facilitate the identification of a new entry point for basic research and subsequent clinical transformation regarding vascular calcification and corresponding clinical evaluation strategies.

Non-alcoholic fatty liver disease (NAFLD) has become a common chronic disease in the world. NAFLD is not only a simple intrahepatic lesion, but also affects the occurrence of a variety of extrahepatic complications. In particular, cardiovascular complications are particularly serious, which is the main cause of death in patients with NAFLD. To study the relationship between NAFLD and AS may be a new way to improve the quality of life in patients with NAFLD. As we all known, inflammatory response plays an important role in the occurrence and development of NAFLD and AS. In this study, we found that the accumulation of Nε-carboxymethyllysine (CML) in the liver leads to hepatic steatosis. CML can induce the expression of interleukin (IL-1β), interleukin (IL-6), tumor necrosis factor (TNF-α), C-reactionprotein (CRP) by binding with advanced glycosylation end-product receptor (RAGE) and accelerate the development of AS. After silencing RAGE expression, the expression of pro-inflammatory cytokines was inhibited and liver and aorta pathological changes were relieved. In conclusion, CML/RAGE signal promotes the progression of non-alcoholic fatty liver disease and atherosclerosis. We hope to provide new ideas for the study of liver vascular dialogue in multi organ communication.

Vascular calcification is an abnormal cell-mediated process in which bone-specific hydroxyapatite crystals are actively deposited on the blood vessel wall and is a significant pathological basis for the increased incidence and mortality of adverse cardiovascular events. Macrophages play an important regulatory role in the occurrence, development, and regression of vascular calcification. After the tissue microenvironment changes, macrophages subsequently change their polarity and phenotype or secrete functional substances as an adaptive response. As research on macrophages continue to move into this field, we gain a new understanding of the mechanism of the formation and regression of vascular calcification, which might offer valuable new intervention targets for the prevention and inhibition of vascular calcification. This review summarizes a wealth of research in this field and explores the roles of macrophages in the development process of vascular calcification.

Background. Macrophage-derived foam cells play a central role in atherosclerosis, and their ultimate fate includes apoptosis, promotion of vascular inflammation, or migration to other tissues. Nε-Carboxymethyl-lysine (CML), the key active component of advanced glycation end products, induced foam cell formation and apoptosis. Previous studies have shown that the Vav1/Rac1 pathway affects the macrophage cytoskeleton and cell migration, but its role in the pathogenesis of diabetic atherosclerosis is unknown. Methods and Results. In this study, we used anterior tibiofibular vascular samples from diabetic foot amputation patients and accident amputation patients, and histological and cytological tests were performed using a diabetic ApoE-/- mouse model and primary peritoneal macrophages, respectively. The results showed that the atherosclerotic plaques of diabetic foot amputation patients and diabetic ApoE-/- mice were larger than those of the control group. Inhibition of the Vav1/Rac1 pathway reduced vascular plaques and promoted the migration of macrophages to lymph nodes. Transwell and wound healing assays showed that the migratory ability of macrophage-derived foam cells was inhibited by CML. Cytoskeletal staining showed that advanced glycation end products inhibited the formation of lamellipodia in foam cells, and inhibition of the Vav1/Rac1 pathway restored the formation of lamellipodia. Conclusion. CML inhibits the migration of foam cells from blood vessels via the Vav1/Rac1 pathway, and this process affects the formation of lamellipodia.

Background. Advanced glycation end products play an important role in diabetic atherosclerosis. The effects of advanced glycation end products (AGEs) on vascular smooth muscle cell- (VSMC-) derived foam cell formation and phenotypic transformation are unknown. Methods. Serological and histological samples were obtained from diabetic amputation patients and accident amputation patients from the Affiliated Hospital of Jiangsu University. CD68/Actin Alpha 2 (ACTA2) coimmunofluorescence sections were used to quantify the number of VSMCs with macrophage-like phenotypes. Western blotting was used to detect the expression of the receptor of advanced glycation end products in vascular samples. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the level of serum Nε-carboxymethyl-lysine (CML). In vitro oil red O staining was used to examine lipid accumulation in VSMCs stimulated by CML. The expression of VSMCs and macrophage markers was measured by western blotting and quantitative real-time PCR. Furthermore, changes in VSMC migration and secretion were detected by the Transwell assay and ELISA. Results. In the arterial plaque sections of diabetic patients, VSMCs transformed to a macrophage-like phenotype. The serum CML and RAGE levels in the plaques were significantly higher in the diabetes group than those in the healthy control group and were significantly related to the number of macrophage-like VSMCs. CML stimulation promoted intracellular lipid accumulation. However, CML stimulation decreased the expression of VSMC markers and increased the expression of macrophage phenotype markers. Finally, CML promoted smooth muscle cell migration and the secretion of proinflammatory-related factors. Conclusions. CML induces VSMC-derived foam cell formation, and VSMCs transdifferentiate to a macrophage-like state, which may be mediated by the activation of RAGE.

Abstract Background Pulmonary hypertension (PH) is a rare disease characterized by proliferation and occlusion of small pulmonary arterioles, which has been associated with a high mortality rate. The pathogenesis of PH is complex and incompletely understood, which includes both genetic and environmental factors that alter vascular structure and function. Methods Thus we aimed to reveal the potential genetic etiology of PH by targeting 143 tag SNPs of 14 candidate genes. Totally 208 individuals from Chinese Han population were enrolled in the present study, including 109 non-idiopathic PH patients and 99 healthy controls. Results The data revealed that 2 SNPs were associated with PH overall susceptibility at p

Advanced glycation end products (AGEs) are closely associated with diabetic macrovascular complications. The present study aimed to investigate the effects of Nε-Carboxymethyl-Lysine (the key active component of AGEs) in diabetic atherosclerosis on foam cell apoptosis and to explore the underlying mechanisms. Tissue sections were collected from 12 Type 2 diabetic patients and 4 control patients who underwent amputation surgery following a car accident. Peritoneal injection of streptozotocin in ApoE−/− mice was used to generate a diabetic model in vivo, and Raw 264.7 cells treated with CML and 740Y-P (a PI3K/AKT signaling agonist) were used to explore the effect of PI3K/AKT signaling in CML-induced foam cell apoptosis in vitro. The anterior tibial section of diabetic amputees contained a thinner fiber cap, higher lipid content, and more apoptotic cells than were found in control patients. in vitro studies using Raw 264.7 cell-derived foam cells and in vivo studies using diabetic ApoE-/- mice showed that CML levels dose-dependently reduced cell vitality, induced foam cell apoptosis and regulated apoptosis related protein. Furthermore, CML significantly decreased the phosphorylation of PI3K/AKT signaling, and restoration of PI3K/AKT signaling by 740Y-P decreased the CML-induced foam cell apoptosis. In conclusion, our results showed CML induced foam cell apoptosis in diabetic atherosclerosis through inhibiting the PI3K/AKT pathway.

Background Excessive angiogenesis is a key feature of vulnerable atherosclerotic plaques, and is considered an independent predictor of cardiovascular risk. CD137 signaling has previously been shown to be involved in atherosclerosis. However, the possible role of CD137 signaling in regulating angiogenesis has not been reported. Methods and Results Apolipoprotein E‐deficient (ApoE−/−) mice were used as the in vivo model of atherosclerosis. Masson and immunohistochemical analysis of atherosclerotic plaques and Matrigel plug assay were used to evaluate the angiogenesis. Human umbilical vein endothelial cells and mouse brain microvascular endothelial cells were used as in vitro and ex vivo models to study how CD137 signaling affects angiogenesis. Matrigel tube formation assay, mouse aortic ring angiogenesis assay, and migration and proliferation assay were employed to assess angiogenesis. Western blot was used to detect protein expression. We found increased neovessel formation in atherosclerotic plaques of ApoE−/− mice treated with agonist anti‐CD137 antibody. Activation of CD137 signaling induced angiogenesis, endothelial proliferation, and endothelial cell migration. CD137 signaling activates the pro‐angiogenic Smad1/5 pathway, induces the phosphorylation of Smad1/5 and nuclear translocation of p‐Smad1/5, which in turn promotes the expression and translocation of NFATc1. Blocking CD137 signaling with inhibitory anti‐CD137 antibody could inhibit this activation and attenuated agonist anti‐CD137 antibody‐induced angiogenesis. Conclusions These findings suggest that CD137 signaling is a new regulator of angiogenesis by modulating the Smad1/5‐NFATc1 pathway.

Our previous study proved that CD137-CD137L interaction can regulate the expression of NFATc1. Here, we investigated whether CD137 signaling regulates the expression of NFATc1 in mice VSMCs through TRAF6/NF-κB p65 pathway. Data shows that the CD137 expression can be stimulated by TNF-α in a time-dependent manner in mouse VSMCs. Knockdown of TRAF6 by siTRAF6 significantly attenuated agonist-CD137mAb induced increase of NF-κB p65 and NFATc1 in VSMCs. Pretreatment with a NF-κB inhibitor PDTC for 30 min inhibited the expression of p-p65 in both cytoplasm and nucleus in VSMCs. Thus, the protein level of NFATc1 can be suppressed through inhibition of p-p65. Finally, we also show that the levels of IL-2 and IL-6 can be increased by agonist-CD137 stimulation and decreased when NFATc1 was suppressed. Our data suggest that activated CD137 signaling regulates the expression of NFATc1 and its downstream factors through TRAF6/NF-κB p65 pathways in VSMCs. These findings provide a novel target for treatment of atherosclerosis.

Inflammation is a common feature in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to assess the influence of thiazolidinedione (TZD) therapy on the circulating levels of inflammatory markers in patients with T2DM.We searched the databases Medline, Embase, ScienceDirect, Web of Science, SpringerLink, and the Cochrane Library for randomized controlled trials (RCTs) that examined the effects of thiazolidinedione vs. a placebo on patients with T2DM. The main outcomes were absolute changes in levels of circulating inflammatory markers. Twenty-seven RCTs were included and data were analyzed using a fixed-effect model or a random-effect model based on heterogeneity. Pooled results indicated that circulating levels of high-sensitivity C reactive protein (hsCRP; SMD = -0.65, 95% CI = -0.98 to -0.32, p < 0.01), monocyte chemoattractant protein-1 (MCP-1; WMD = -54.19, 95% CI = -73.86 to -34.52, p < 0.01), von Willebrand factor% (vWF%; WMD = -8.18, 95% CI = -13.54 to -2.81, p 0.01), fibrinogen (SMD = -0.26, 95% CI = -0.41 to -0.11, p < 0.01) and E-selectin(WMD = -3.57, 95% CI = -5.59 to -1.54, p

BACKGROUND: Our previous studies showed that increased levels of cyclophilin A (CyPA) may be a valuable marker for predicting the severity of acute coronary syndromes and that interruption of CD137-CD137L interactions diminished the formation and progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Here, we sought to determine whether the proinflammatory factor CyPA is involved in atherosclerosis regulated by CD137-CD137L interactions. METHODS AND RESULTS: A constrictive collar was placed around the right carotid arteries of ApoE-/- mice that were fed a high-fat diet to induce atherosclerotic plaque formation. After that, the mice were intraperitoneally injected with anti-CD137 or anti-CD137L in the presence or absence of the recombinant lentiviral vectors LVTHM-CyPA or pGC-FU-CyPA, respectively. Interestingly, activation of CD137-CD137L was negatively correlated with CyPA expression in vivo and in vitro. Stimulating CD137-CD137L interaction significantly increased CyPA, which was concurrent with the upregulation of proinflammatory cytokines, chemokines and matrix metalloproteinases and resulted in the promotion of atherosclerosis in ApoE-/- mice. Silencing CyPA could eliminate these effects, and restoration of CyPA effectively and consistently attenuated the atherosclerotic suppression phenotypes elicited by the blockade of CD137-CD137L. CONCLUSION: These observations suggest that CD137-CD137L interactions mediated via regulation of CyPA contribute to the progression of atherosclerosis.

BACKGROUND: N(ε)-carboxymethyl-lysine (CML) is a major advanced glycation end-product (AGEs) widely found in foods. The aim of our study was to evaluate how exogenous CML-peptide is dynamically absorbed from the gastrointestinal tract and eliminated by renal tubular secretion using microPET imaging. METHODS: The present study consisted of three investigations. In study I, we synthesized the imaging tracer (18)F-CML by reacting N-succinimidyl 4-(18)F-fluorobenzoate ((18)F-SFB) with CML. In study II, the biological activity of (18)F-CML was evaluated in RAW264.7 cells and HepG2 cells. In study III, the biodistribution and elimination of AGEs in ICR mice were studied in vivo following tail vein injection and intragastric administration of (18)F-CML. RESULT: The formation of (18)F-CML was confirmed by comparing its retention time with the corresponding reference compound (19)F-CML. The radiochemical purity (RCP) of (18)F-CML was >95%, and it showed a stable character in vitro and in vivo. Uptake of (18)F-CML by RAW264.7 cells and HepG2 cells could be inhibited by unmodified CML. (18)F-CML was quickly distributed via the blood, and it was rapidly excreted through the kidneys 20 min after tail vein injection. However, (18)F-CML was only slightly absorbed following intragastric administration. After administration of (18)F-CML via a stomach tube, the radioactivity was completely localized in the stomach for the first 15 min. At 150 min post intragastric administration, intense accumulation of radioactivity in the intestines was still observed. CONCLUSIONS: PET technology is a powerful tool for the in vivo analysis of the gastrointestinal absorption of orally administered drugs. (18)F-CML is hardly absorbed by the gastrointestinal tract. It is rapidly distributed and eliminated from blood following intravenous administration. Thus, it may not be harmful to healthy bodies. Our study showed the feasibility of noninvasively imaging (18)F-labeled AGEs and was the first to describe CML-peptide gastrointestinal absorption by means of PET.