Atherosclerosis (AS)-associated cardiovascular disease is the main cause of global mortality. The excessive retention of glycated low-density lipoprotein (G-LDL) under the vascular endothelium promotes AS. In addition, G-LDL supports a role in promoting the expression of scavenger receptor A (SR-A), increasing SR-A-mediated transcytosis of G-LDL in endothelial cells (ECs), consequently accelerating the progression of atherosclerosis. However, the underlying mechanism used by G-LDL to promote SR-A expression has not been elucidated, thus representing the aim of this work. The protein–protein interaction of the E3 SUMO ligase KRAB structural domain-associated protein 1 (KAP1) and SR-A were confirmed by co-immunoprecipitation (co-IP)-based immunoblotting and immunofluorescence in human umbilical vein endothelial cells (HUVECs). G-LDL uptake and transcytosis in KAP1-silencing or overexpressing HUVECs were assessed. The effect of KAP1 on de-ubiquitination and SUMOylation of SR-A was determined by co-IP-based immunoblotting. The role of KAP1 on G-LDL-induced atherosclerosis was tested by adenovirus-mediated knockdown in ApoE−/− mice. KAP1 was identified as an enhancer of SR-A, promoting its expression. KAP1 bound to SR-A and promoted SUMO1 modification of the SR-A lysine (K)22, which hampers K48-linked ubiquitination and proteasomal degradation of SR-A. KAP1 deficiency attenuated G-LDL-induced SR-A activation both in vitro and in vivo, reduced aortic G-LDL retention, and consequently, atherosclerotic vulnerable plaque formation in murine models. This study identifies a SUMOylation–ubiquitination crosstalk that governs SR-A stability, revealing KAP1 as a key molecular switch controlling SR-A turnover in endothelial cells. These findings provide a mechanistic basis for how G-LDL accelerates atherosclerosis.

Atherosclerosis is attributable to a series of diabetes-related complications. CAV1 (caveolin 1)-mediated low-density lipoprotein (LDL) particle transcytosis across endothelial cells (ECs) is the initial step of atherosclerosis. MAP1LC3/LC3-interacting regions in the intramembrane domain (IMD) of CAV1 were buried in the caveolae and were not accessible for LC3B interaction, protecting CAV1 from autophagic degradation. However, the CSD domain of CAV1, exposed in the cytosol, directly interacted with a CBM domain of LC3B and inhibited autophagy. Therefore, the peptide IMD-CBM was constructed to induce the selective autophagic degradation of CAV1 and suppress LDL transcytosis in diabetic atherosclerosis. EC-specific expression of IMD-CBM was achieved using adenovirus. IMD-CBM directly interacted with CAV1 and LC3B in ECs, leading to the selective autophagic degradation of CAV1, activation of autophagy, and subsequent inhibition of LDL transcytosis. IMD-CBM promoted the autophagic degradation of CAV1 and consequently reduced the area of atherosclerotic plaques in apoe-/- diabetic atherosclerotic mice. Overall, IMD-CBM expedited the autophagic degradation of CAV1 and inhibited high glucose-induced LDL transcytosis, highlighting its potential as a novel translatable strategy for the management of diabetic atherosclerosis.Abbreviations: ACTB: actin beta; AKT/protein kinase B: AKT serine/threonine kinase; AMPK: 5'-adenosine monophosphate-activated protein kinase; CAV1: caveolin 1; CBM: CAV1-binding motif; CRP: C-reactive protein; CSD: CAV1-scaffolding domain; GFP: green fluorescent protein; HUVEC: human umbilical vein endothelial cell; EC: endothelial cell; FITC: fluorescein isothiocyanate; IL6: interleukin 6; IL10: interleukin 10; IMD: intramembrane domain; LDL: low-density lipoprotein; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NFKB/NF-κB: nuclear factor kappa B; NFKBIA/IκBα: NFKB inhibitor alpha; NO: nitric oxide; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PIK3C3/VPS34: phosphatidylinositol-3-kinase catalytic subunit type 3; Rapa: rapamycin; SAA: serum amyloid A; SQSTM1/p62: sequestosome 1; STZ: streptozotocin; TEM: transmission electron microscopy; TNF/TNF-α: tumor necrosis factor.

Diabetic vascular complications are common and severe, worsening quality of life and long-term outcomes. In diabetes, chronic hyperglycemia together with dyslipidemia and hypertension reshapes endothelial metabolism and homeostasis. Endothelial cells shift the balance of glucose utilization, fatty acid oxidation, and mitochondrial function, and these metabolic changes bias endothelial behavior toward reduced nitric oxide bioavailability, oxidative stress, and a pro-inflammatory, pro-thrombotic state. Over time, maladaptive stress responses promote senescence, cell loss, and endothelial-to-mesenchymal transition, accelerating the initiation and progression of atherosclerotic plaques. This review summarizes how diabetic cues drive endothelial metabolic reprogramming and how this, in turn, links endothelial dysfunction to plaque formation, growth, and instability. We highlight key metabolic pathways and discuss how local hemodynamic forces at athero-prone regions further shape endothelial phenotypes and inflammatory signaling. Finally, we outline therapeutic opportunities that target endothelial metabolism and stress responses-including modulation of glycolytic flux, mitochondrial and redox-directed strategies, and pathway-level interventions that curb hypoxia and inflammatory programs. We emphasize translational priorities such as endothelium-selective delivery, biomarkers of endothelial metabolic state, and rigorous clinical testing to enable earlier and more effective prevention of diabetes-associated atherosclerotic disease.

Erythritol is a widely used low-calorie sugar substitute, but its relationship with cerebrovascular risk remains uncertain. We investigated the association between genetically predicted erythritol levels and ischemic stroke and explored stroke-related molecular features using an integrative bioinformatics framework. Two-sample and multivariable Mendelian randomization were performed across cardiovascular–kidney–metabolic outcomes, followed by target prediction, enrichment and protein–protein interaction analyses, transcriptomic profiling, machine-learning feature selection, SHAP interpretation, immune-cell analysis, gene set variation analysis, and exploratory molecular docking. Genetically predicted erythritol showed the strongest association with stroke among the tested sweetener-related traits (OR = 1.246, 95% CI: 1.101–1.410, p < 0.001) and remained significant after adjustment for selected hemodynamic, glycometabolic, and lipid-related traits. Downstream analyses highlighted inflammatory, oxidative-stress, hypoxic, and vascular-injury pathways and prioritized MMP9, TLR4, and HIF1A as a reproducible stroke-related three-gene signature. These downstream bioinformatic findings are exploratory and do not establish erythritol-specific molecular regulation. Overall, the results support an association between genetically predicted erythritol levels and ischemic stroke and identify candidate pathways and genes for further investigation; the MR exposure should not be interpreted as direct evidence that dietary erythritol intake causes stroke.

BackgroundThis study aims to evaluate the correlation between the uric acid (UA) to albumin (ALB) ratio (UAR) and carotid atherosclerosis (CAS) in patients with type 2 diabetes mellitus (T2DM), as well as to assess the predictive value of UAR for CAS.MethodsA cross-sectional, single-center study was conducted, retrospectively analyzing hematological parameters from 259 T2DM patients with CAS (T2DM-CAS) and 131 T2DM patients without CAS (T2DM-WCAS). Carotid intima-media thickness (IMT) and carotid plaques (CAP) were measured using Doppler ultrasound.ResultsThe UAR level in the T2DM-CAS group was significantly higher than that in the T2DM-WCAS group (P < 0.001). Multivariate logistic regression analysis revealed that UAR is an independent risk factor for T2DM-CAS (P < 0.001). The area under the ROC curve (AUC) for UAR in predicting T2DM-CAS was 0.712, with a Youden index of 0.278.ConclusionHigh levels of UAR are closely associated with the occurrence of T2DM-CAS and may serve as a useful biomarker for predicting T2DM-CAS.

Mounting evidence indicates that gut microbial metabolites are central hubs linking the gut microbiota to atherosclerosis (AS). Gut microbiota enriched with pathobiont bacteria responsible for producing metabolites like trimethylamine N-oxide and phenylacetylglutamine are related to an increased risk of cardiovascular events. Furthermore, gut microbiota enriched with bacteria responsible for producing short-chain fatty acids, indole, and its derivatives, such as indole-3-propionic acid, have demonstrated AS-protective effects. This study described AS-related gut microbial composition and how microbial metabolites affect AS. Summary findings revealed gut microbiota and their metabolites-targeted diets could benefit AS treatment. In conclusion, dietary interventions centered on the gut microbiota represent a promising strategy for AS treatment, and understanding diet-microbiota interactions could potentially be devoted to developing novel anti-AS therapies.

Objective Caveolae are closely linked to the onset and progression of atherosclerosis. The pivotal involvement of caveolin-1 (CAV1) within the caveolae in atherosclerosis development has been consistently supported. However, the potential contributions of additional caveolae proteins to atherosclerosis necessitate further exploration. Therefore, this research aimed to afford clinical evidence linking CAVIN-2 to diabetic peripheral artery disease (PAD) and its role in low-density lipoprotein (LDL) transcytosis.Methods Blood samples were collected from a total of 115 participants, including 36 patients without diabetes (ND), 26 patients with type 2 diabetes mellitus (T2DM), and 53 patients with T2DM and PAD (DM-PAD). The plasma levels of CAV1, CAVIN-1, and CAVIN-2 were measured by ELISA. The correlation between CAV1, CAVIN-1, CAVIN-2, and diabetic PAD was examined using Spearman correlation analysis. The predictive effect of CAV1 and CAVIN-2 were analyzed by receiver operating characteristic (ROC) curves. Cellular experiments were used to investigate the effect and mechanism of CAVIN-2 on LDL transcytosis.Results Elevated CAV1 and CAVIN-2 levels were observed in T2DM and DM-PAD groups, with a positive correlation to DM-PAD and PAD severity. Both CAV1 and CAVIN-2 emerged as predictors of DM-PAD. In vitro, CAVIN-2 knockdown decreased LDL transcytosis, while CAVIN-2 overexpression increased it. Additionally, CAVIN-2 was found to inhibit eNOS activation and nitric oxide (NO) production, thereby promoting LDL transcytosis and atherosclerosis progression.Conclusion CAVIN-2 was positively correlated with DM-PAD and promoted LDL transcytosis through the inhibition of eNOS activation, contributing to atherosclerosis development. This study provided clinical evidence linking CAVIN-2 to diabetic PAD and suggested its potential as a biomarker for disease progression.

Uric acid (UA) to high-density lipoprotein (HDL) ratio (UHR) has recently been proposed as a novel biomarker of inflammation. This study aimed to investigate the association between the UHR and carotid atherosclerosis (CAS) in patients with type 2 diabetes mellitus (T2DM). In this single-center, retrospective cross-sectional study, 379 patients with T2DM were enrolled and categorized into two groups: 259 T2DM patients with CAS (T2DM-CAS) and 120 T2DM patients without CAS (T2DM-WCAS). Carotid intima‒media thickness (CIMT) and carotid atheromatous plaques (CAPs) were assessed via Doppler ultrasound. UHR values were compared between the groups, and receiver operating characteristic (ROC) curve analysis was employed to evaluate their diagnostic performance. The UHR was significantly greater in the T2DM-CAS group than in the T2DM-WCAS group (P < 0.001). Multivariate logistic regression analysis identified the UHR as an independent risk factor for T2DM-CAS (P < 0.001). The area under the ROC curve (AUC) for UHR to detect CAS was 0.750, with an optimal cut-off value of 0.35. The UHR is an independent risk factor for CAS in patients with T2DM and may serve as a valuable biomarker for predicting CAS in this population.

Chronic stress is a critical risk factor for depression, and prolonged exposure to stressors increases the risk of metabolic dysregulation. Gut microbiota (GM) intervention is a promising therapeutic target for stress-related emotional and behavioral disorders. In the present study, we apply compound lactic acid bacteria (CLAB) (Lacticaseibacillus rhamnosus GG and Enterococcus faecium) administration therapy to investigate the effect of gut microbiota (GM) on chronic restraint stress (CRS)-depression and its related glucose-lipid metabolism disturbance. We established a non-human primate model of CRS depression to mimic the depressive state in humans and applied CLAB for gastric gavage treatment. CRS macaques exhibit marked depressive-like behavior and disrupted GM structure, decreased levels of C1q/tumor necrosis factor-related protein 9 (CTRP9) and increased levels of CTRP5, and induced insulin resistance (IR) and lipid metabolism disorders. Treatment with CLAB normalized GM structure in CRS macaques, increased the abundance of Lactobacillus murinus and Lactobacillus reuteri, and reduced depressive-like behavior in CRS macaques, with a rebound in CTRP9 and HDL-C levels, reduced CTRP5 and TG levels and improved IR. In addition, CLAB may serve as a promising non-pharmacological intervention that alleviates depression-related metabolic dysregulation by modulating the gut microbiota and improving lipid and glucose metabolism.

BACKGROUND:Excessive subendothelial retention of oxidized low-density lipoprotein (oxLDL) and subsequent oxLDL engulfment by macrophages leads to the formation of foam cells and the development of atherosclerosis. Our previous study showed that the plasma level of sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5) was a novel biomarker for the prognosis of atherosclerosis in diabetic patients. However, the role and underlying mechanisms of Siglec-5 in atherosclerosis have not been elucidated. METHODS:The interaction between oxLDL and Siglec-5 was detected by fluorescence colocalization and coimmunoprecipitation. The effect of oxLDL on Siglec-5 expression was detected in endothelial cells and macrophages, and the effect of Siglec-5 on oxLDL transcytosis and uptake was investigated. Siglec-5 was overexpressed in mice using recombinant adeno-associated virus vector serotype 9 (rAAV9-Siglec-5) to evaluate the effect of Siglec-5 on oxLDL uptake and atherogenesis in vivo. In addition, the effects of Siglec-5 antibodies and soluble Siglec-5 proteins on oxLDL transcytosis and uptake and their role in atherogenesis were investigated in vivo and in vitro. RESULTS:We found that oxLDL interacted with Siglec-5 and that oxLDL stimulated the expression of Siglec-5. Siglec-5 promotes the transcytosis and uptake of oxLDL, while both anti-Siglec-5 antibodies and soluble Siglec-5 protein attenuated oxLDL transcytosis and uptake. Interestingly, overexpression of Siglec-5 by recombinant adeno-associated viral vector serotype 9 (rAAV9-Siglec-5) promoted the retention of oxLDL in the aorta of C57BL/6 mice. Moreover, overexpression of Siglec-5 significantly accelerated the formation of atherosclerotic lesions in Apoe-/- mice. Moreover, both anti-Siglec-5 antibodies and soluble Siglec-5 protein significantly alleviated the retention of oxLDL in the aorta of rAAV9-Siglec-5-transfected C57BL/6 mice and the formation of atherosclerotic plaques in rAAV9-Siglec-5-transfected Apoe-/- mice. CONCLUSION:Our results suggested that Siglec-5 was a novel receptor that mediated oxLDL transcytosis and promoted the formation of foam cells. Interventions that inhibit the interaction between oxLDL and Siglec-5, including anti-Siglec-5 antibody or soluble Siglec-5 protein treatment, may provide novel therapeutic strategies in treating atherosclerosis.

BACKGROUND: Integrins mediate the adhesion, crawling, and migration of neutrophils during vascular inflammation. Thiol exchange is important in the regulation of integrin functions. ERp72 (endoplasmic reticulum–resident protein 72) is a member of the thiol isomerase family responsible for the catalysis of disulfide rearrangement. However, the role of ERp72 in the regulation of Mac-1 (integrin αMβ2) on neutrophils remains elusive. METHODS: Intravital microscopy of the cremaster microcirculation was performed to determine in vivo neutrophil movement. Static adhesion, flow chamber, and flow cytometry were used to evaluate in vitro integrin functions. Confocal fluorescent microscopy and coimmunoprecipitation were utilized to characterize the interactions between ERp72 and Mac-1 on neutrophil surface. Cell-impermeable probes and mass spectrometry were used to label reactive thiols and identify target disulfide bonds during redox exchange. Biomembrane force probe was performed to quantitatively measure the binding affinity of Mac-1. A murine model of acute lung injury induced by lipopolysaccharide was utilized to evaluate neutrophil-associated vasculopathy. RESULTS: ERp72-deficient neutrophils exhibited increased rolling but decreased adhesion/crawling on inflamed venules in vivo and defective static adhesion in vitro. The defect was due to defective activation of integrin Mac-1 but not LFA-1 (lymphocyte function-associated antigen-1) using blocking or epitope-specific antibodies. ERp72 interacted with Mac-1 in lipid rafts on neutrophil surface leading to the reduction of the C654-C711 disulfide bond in the αM subunit that is critical for Mac-1 activation. Recombinant ERp72, via its catalytic motifs, increased the binding affinity of Mac-1 with ICAM-1 (intercellular adhesion molecule-1) and rescued the defective adhesion of ERp72-deficient neutrophils both in vitro and in vivo. Deletion of ERp72 in the bone marrow inhibited neutrophil infiltration, ameliorated tissue damage, and increased survival during murine acute lung injury. CONCLUSIONS: Extracellular ERp72 regulates integrin Mac-1 activity by catalyzing disulfide rearrangement on the αM subunit and may be a novel target for the treatment of neutrophil-associated vasculopathy.

Background: Controversy persists regarding the effects of sodium -glucose cotransporter 2 (SGLT2) inhibitors on cancer. The underlying causal relationship remains unclear. Method: A two -sample Mendelian randomization (MR) strategy was employed to investigate the causal associations between SGLT2 inhibitors and 26 site -specific malignancies. Instrumental variants strongly associated with SLC5A2 gene expression and glycated hemoglobin A1c levels were identified as the genetic proxy for SGLT2 inhibition. Cancer -related outcome datasets sourced from the OpenGWAS project were separated into discovery and replication datasets. The meta -analysis was conducted to determine the final causality. Results: Genetically proxied SGLT2 inhibition showed a significant association with bronchial and lung cancer (beta: -0.028 [ -0.041, -0.015], P < 0.001), bladder cancer (beta: 0.018 [0.008, 0.027], P < 0.001), prostate cancer (beta: 1.168 [0.594, 1.742], P < 0.001), cervical cancer (beta: -0.019 [ -0.031, -0.008], P = 0.001), corpus uterine cancer (beta: 0.015 [0.006, 0.025], P = 0.001) and non -melanoma skin cancer (beta: -0.080 [ -0.116, -0.044], P < 0.001) in the discovery cohort. The suggestive causal effect of SGLT2 inhibition on the increased risk of cervical cancer (beta: 3.241 [0.855, 5.627], P = 0.008) and lymphoid leukemia (beta: 4.126 [0.383, 7.868], P = 0.031) was found in the replication cohort. The combined causality of the following types of cancer was observed to remain significant after meta -analysis: bronchial and lung cancer, bladder cancer, prostate cancer, corpus uterine cancer, and non -melanoma skin cancer (all P <= 0.001). Conclusion: For the first time we discovered that the SGLT2 inhibition may exert protection on bronchial and lung cancer and non -melanoma skin cancer from a genetic perspective. However, suggestive higher cancer risks of bladder, prostate, and corpus uteri were also noted, which warrants real -world data validation in the future.

Abstract The essence of difference between hemostasis and thrombosis is that the clotting reaction is a highly fine-tuned process. Vascular protein disulfide isomerase (PDI) represents a critical mechanism regulating the functions of hemostatic proteins. Herein we show that histidine-rich glycoprotein (HRG) is a substrate of PDI. Reduction of HRG by PDI enhances the procoagulant and anticoagulant activities of HRG by neutralization of endothelial heparan sulfate (HS) and inhibition of factor XII (FXIIa) activity, respectively. Murine HRG deficiency (Hrg −/− ) leads to delayed onset but enhanced formation of thrombus compared to WT. However, in the combined FXII deficiency (F12 −/− ) and HRG deficiency (by siRNA or Hrg −/− ), there is further thrombosis reduction compared to F12 −/− alone, confirming HRG’s procoagulant activity independent of FXIIa. Mutation of target disulfides of PDI leads to a gain-of-function mutant of HRG that promotes its activities during coagulation. Thus, PDI-HRG pathway fine-tunes thrombosis by promoting its rapid initiation via neutralization of HS and preventing excessive propagation via inhibition of FXIIa.

Aims Mounting evidence has shown that caveolin-1 plays a pathological role in the progression of albuminuria. Our study aimed to provide clinical evidence showing whether circulating caveolin-1 levels were associated with microalbuminuria (MAU) in women with overt diabetes mellitus in pregnancy (ODMIP). Methods A total of 150 pregnant women were enrolled in different groups, including 40 women with ODMIP and MAU (ODMIP + MAU), 40 women with ODMIP, and 70 women without ODMIP (Non-ODMIP). Plasma caveolin-1 levels were determined by ELISA. The presence of caveolin-1 in the human umbilical vein vascular wall was evaluated by immunohistochemical and western blot analysis, respectively. Albumin transcytosis across endothelial cells was measured using an established nonradioactive in vitro approach. Results Significantly increased levels of plasma caveolin-1 were detected in ODMIP + MAU women. The Pearson’s correlation analysis revealed a positive correlation between plasma caveolin-1 levels and Hemoglobin A1c (HbA1c %) as well as with MAU in the ODMIP + MAU group. Simultaneously, experimental knockdown or overexpression of caveolin-1 significantly decreased or increased the level of albumin transcytosis across both human and mouse glomerular endothelial cells (GECs), respectively. Conclusions Our data showed a positive association between plasma caveolin-1 levels and microalbuminuria in ODMIP + MAU.

BackgroundNeutrophil/high-density lipoprotein (HDL) ratio (NHR), monocyte/HDL ratio (MHR), lymphocyte/HDL ratio (LHR), platelet/HDL ratio (PHR), systemic immune-inflammation index (SII), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) have been recently investigated as novel inflammatory markers. Herein, the correlation was investigated between these inflammatory biomarkers and peripheral arterial disease (PAD) in type 2 diabetes mellitus (T2DM) patients.MethodsIn this retrospective observational study, the hematological parameter data of 216 T2DM patients without PAD (T2DM-WPAD) and 218 T2DM patients with PAD (T2DM-PAD) at Fontaine stages II, III or IV stage had been collected. Differences in NHR, MHR, LHR, PHR, SII, SIRI, and AISI were analyzed, and receiver operating characteristic (ROC) curves were used to analyze the diagnostic potential of these parameters.ResultsThe levels of NHR, MHR, PHR, SII, SIRI and AISI in T2DM-PAD patients were significantly higher than in T2DM-WPAD patients (P < 0.001). They were correlated with disease severity. Further, multifactorial logistic regression analyses showed that higher NHR, MHR, PHR, SII, SIRI, and AISI might be independent risk factors for T2DM-PAD (P < 0.001). The areas under the curve (AUCs) of the NHR, MHR, PHR, SII, SIRI, and AISI for T2DM-PAD patients was 0.703, 0.685, 0.606, 0.648, 0.711, and 0.670, respectively. The AUC of the NHR and SIRI combined model was 0.733.ConclusionThe levels of NHR, MHR, PHR, SII, SIRI, and AISI were higher in T2DM-PAD patients, and they were independently linked with its clinical severity. The combination model of NHR and SIRI was most valuable for predicting T2DM – PAD.

EDITORIAL article Front. Endocrinol., 12 January 2023Sec. Cellular Endocrinology Volume 13 - 2022 | https://doi.org/10.3389/fendo.2022.1114632