Markers Of Vascular Inflammation Research Articles

Whole Body Vibration Training Has No Effect on Vascular Endothelial and Inflammatory Markers in Young Healthy Women

Whole Body Vibration Training Has No Effect on Vascular Endothelial and Inflammatory Markers in Young Healthy Women

The beneficial effects of monoglucosyl hesperidin and monoglucosyl rutin on vascular flexibility: a randomized, placebo-controlled, double-blind, parallel-group study

Background: There is mounting evidence that the intake of polyphenols can help prevent cardiovascular complications. Furthermore, multiple intakes of different polyphenol compounds are expected to have a synergistic effect. However, few studies have examined the preventive effect of simultaneous polyphenol intake on cardiovascular complications in healthy adults. Objective: The present study aimed to evaluate the efficacy of daily intake of 70 mg of monoglucosyl hesperidin (MH) alone, or in combination with 140 mg of monoglucosyl rutin (MR), in improving vascular flexibility. Methods: This 8-week study was conducted on 66 healthy male and female participants with a relatively high body mass index (BMI) and low vascular flexibility. The participants were randomly assigned to an MH group (MH alone), MHMR group (combination of MH and MR), or placebo group by a computer-generated list (each n = 22). Participants took two tablets per day of either MH, MHMR or placebo during the intervention. Outcomes included vascular function indices, capillary flow, and inflammatory markers. Assessment points were at 4 weeks (4w) and 8 weeks (8w) of the intervention. Results: The primary outcome was flow-mediated dilation. In an analysis including participants whose left brachial-ankle pulse wave velocity (baPWV) was ≥1232.5 cm/s at baseline in the per-protocol set, the MHMR group showed significant improvement compared with the placebo group in flow-mediated dilation, maximum post-avascularization artery diameter, baPWV (each and average of both legs), and E-selectin at 8w. Conclusion: These results indicated that MH, in combination with MR, may act on vascular endothelial cells to improve vascular flexibility in healthy adults with a relatively lowvascular flexibility. (UMIN000046054). Keywords: Monoglucosyl hesperidin; Monoglucosyl rutin; flow-mediated dilation; E-selectin; pulse wave velocity, body mass index, vascular flexibility

Markers of vascular inflammation in pregnant women with gestational diabetes

Markers of vascular inflammation in pregnant women with gestational diabetes

Porphyromonas gingivalis Infection is Associated with Increased Vascular Inflammation in Patients with and Without Coronary Artery Disease

Vascular inflammation is a critical measure of risk for major adverse cardiac events in patients with and without known coronary artery disease. It is recognized that patients with poor oral hygiene tend to have an increased prevalence of coronary artery disease and myocardial infarction. Porphyromonas gingivalis (PG) is the keystone pathogen leading to periodontal disease. Despite evidence suggesting a link between active PG infection and coronary artery disease, there is limited data investigating whether PG can contribute to increased markers of vascular inflammation in patients with coronary artery disease. In this study, we studied 112 consecutive patients who presented at a community preventive cardiology clinic who consented to be assessed for the presence of PG. Subjects were enrolled in a mouth along assessment with measures of vascular inflammation, which was part of their routine clinical care. The average age of patients was 70.4 ± 8.5 years with 48.6% of the patients positive for PG and 20.5% with a history of coronary artery disease (CAD). The distribution of PG positivity was 48.3% and 34.8% in patients without and with a history of CAD, respectively. Patients with CAD have significantly greater levels of high sensitivity C-reactive protein (hsCRP_ (1.3 ± 0.3 vs. 3.2 ± 1.1 mg/dL, p = 0.04) and MPO (245.1 ± 19.4 vs. 371.4 ± 39.1 pmol/L, p = 0.003). Patients without a history of CAD, only Myeloperoxidase (MPO) was significantly increased. Statin use was significantly greater in those patients with a history of CAD. Interestingly, statin use tended to be greater in PG+ patients (71% vs. 62%) regardless of CAD status. The data from this early study demonstrate a link between active PG infection and increase in markers of vascular inflammation, especially in patients with established CAD. The findings suggest PG as a marker of cardiovascular risk, especially in patients with residual inflammatory risk.

Short, frequent, light-intensity walking activity improves postprandial vascular-inflammatory biomarkers in people with type 1 diabetes: The SIT-LESS randomized controlled trial.

To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D). In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1β, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status. Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1β, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1β, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1β (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D. Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D. The trial was prospectively registered (ISRCTN13641847).

Expression of hTERT and Lp-PLA(2) genes is increased in primary hypothyroidism.

ObjectiveSightly low serum free T4 levels are associated with longer life expectancy. However, hypothyroidism is associated with increased risk of inflammation and vascular complications. Therefore, relation of thyroid hormones (THs) with life expectancy seems to be complex. This study was carried out in an effort to understand the contribution of THs in inflammation and aging. Methodology15 cases of treatment naïve primary hypothyroidism and 15 age and sex matched euthyroid controls were recruited. mRNA expression of Telomerase (hTERT), leucocyte telomere length (LTL) and Lipoprotein associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation and risk predictor of cardiovascular events were measured by qPCR in whole blood. ResultExpression of hTERT was found to be 6.95 times higher in the cases as compared to the controls. mRNA expression of Lp-PLA(2) was also 3.3 times higher in cases. LTL in euthyroid was approximately 81% of the length in hypothyroid patients. ConclusionA higher expression of hTERT indicates that hypothyroidism confers better cell survival in peripheral leucocytes inspite of the presence of vascular inflammation. However causal relationship cannot be ascertained with these results.

Higher Noncalcified Plaque Volume Is Associated With Increased Plaque Vulnerability and Vascular Inflammation.

Recently, it was reported that noncalcified plaque (NCP) volume was an independent predictor for cardiac events. Pericoronary adipose tissue (PCAT) attenuation is a marker of vascular inflammation and has been associated with increased cardiac mortality. The aim of this study was to evaluate the relationships between NCP volume, plaque vulnerability, and PCAT attenuation. Patients who underwent preintervention coronary computed tomography angiography and optical coherence tomography were enrolled. Plaque volume was measured by computed tomography angiography, plaque vulnerability by optical coherence tomography, and the level of coronary inflammation by PCAT attenuation. The plaques were divided into 2 groups of high or low NCP volume based on the median NCP volume. Among 704 plaques in 454 patients, the group with high NCP volume had a higher prevalence of lipid-rich plaque (87.2% versus 75.9%; P<0.001), thin-cap fibroatheroma (38.1% versus 20.7%; P<0.001), macrophage (77.8% versus 63.4%; P<0.001), microvessel (58.2% versus 42.9%; P<0.001), and cholesterol crystal (42.0% versus 26.7%; P<0.001) than the group with low NCP plaque volume. The group with high NCP volume also had higher PCAT attenuation than the group with low NCP volume (-69.6±10.0 versus -73.5±10.6 Hounsfield unit; P<0.001). In multivariable analysis, NCP volume was significantly associated with thin-cap fibroatheroma and high PCAT attenuation. In the analysis of the combination of PCAT attenuation and NCP volume, the prevalence of thin-cap fibroatheroma was the highest in the high PCAT attenuation and high NCP volume group and the lowest in the low PCAT attenuation and low NCP volume group. Higher NCP volume was associated with higher plaque vulnerability and vascular inflammation. The combination of PCAT attenuation and NCP volume may help identify plaque vulnerability noninvasively. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.

The BET inhibitor apabetalone decreases neuroendothelial proinflammatory activation in vitro and in a mouse model of systemic inflammation.

Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of in vitro endothelial activation, including monocyte chemoattractant protein-1 (MCP-1) and RANTES chemokine secretion, cell surface expression of endothelial cell adhesion molecule VCAM-1, as well as endothelial capture of THP-1 monocytes in static and shear stress conditions. Apabetalone pretreatment of THP-1 downregulates cell surface expression of chemokine receptors CCR1, CCR2, and CCR5, and of the VCAM-1 cognate receptor, integrin α4. Consequently, apabetalone reduces THP-1 chemoattraction towards soluble CCR ligands MCP-1 and RANTES, and THP-1 adhesion to activated BMVECs. In a mouse model of brain inflammation, apabetalone counters lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, consistent with decreased neuroendothelial inflammation. In conclusion, apabetalone decreases proinflammatory activation of brain endothelial cells and monocytes in vitro and in the mouse brain during systemic inflammation.

Molecular imaging of large vessel vasculitis

Large vessel vasculitis (LVV) affects mainly large arteries with giant cell arteritis (GCA) and Takayasu arteritis (TAK) being the two most frequent forms. Clinical symptoms can be non-specific, including headache, fatigue, weight loss, and change in vision. Untreated, LVV may also lead to serious complications such as blindness, aortic aneurysm and dissection. Therefore, rapid recognition of the disease leading to accurate diagnosis and appropriate treatment is essential. FDG-PET/CT imaging has emerged as a sensitive marker of active vascular inflammation and its use in the management of LVV is now integrated in guidelines. In this article, we will discuss the role of FDG-PET/CT for the diagnosis of LVV and monitoring of therapy, as well as review technical and interpretation parameters.

The vitamin-k-cycle-enzyme VKORC1L1, but not its isoenzyme VKORC1, reduces inflammation in coronary endothelial cells

Abstract Introduction Vascular inflammation is a crucial contributor to atherosclerosis, in which oxidative stress, endoplasmic reticulum (ER) stress and transition of endothelial to mesenchymal cells (EndMT) are of critical importance. Vitamin-K-antagonists (VKA) promote vascular dysfunction, while vitamin K intake was proposed to reduce incidence of coronary artery disease. Key enzyme for regeneration of vitamin K is the Vitamin K epoxide reductase complex subunit 1 (VKORC1), which also represents the pharmacological target of VKA. VKOR-like1 (VKORC1L1) is an isoenzyme of VKORC1, which resides at the ER-membrane, exerts antioxidative properties and is involved in vitamin K maintenance. Aim of this study was to investigate the role of VKORC1 and VKORC1L1 in inflammation of human coronary artery endothelial cells (HCAEC). Methods and Results In silico analyses of the proteome of human coronary atherosclerosis revealed increased expression of VKORC1L1, but not of VKORC1. In vitro induction of oxidative stress (H2O2) and ER-Stress (tunicamycin) in HCAEC promoted time- and dose-dependent enhanced expression of VKORC1L1, without altering VKORC1 expression (H2O2: 2.3-fold vs. 0.8-fold after 40 minutes, p=0.04; tunicamycin: 1 μg/ml: 1.43-fold vs. 0.8-fold, p&amp;lt;0.01). Moreover, inducing EndMT by treatment with a differentiation medium (containing TGF-ß2, IL-1ß) resulted in a reduction of VKORC1L1, but not of VKORC1 (Fig.1). To analyze the relevance of the VKOR-enzymes on endothelial cell function, VKORC1 and VKORC1L1 were downregulated by siRNA. VKORC1L1 downregulation increased formation of reactive oxygen species (ROS) (DCFDA signal: 0.98-fold vs. 1.31-fold, p = 0.03) and reduced proliferation (EdU signal: 0.56 ± 0.02 vs. control, p &amp;lt; 0.01), whereas viability of HCAEC remained unchanged. ELISA and qPCR experiments revealed enhanced expression of a variety of markers of vascular inflammation after VKORC1L1 (e.g., IL-6: 3.42-fold ± 0.53, NF-κB: 1.95-fold ± 0.13, VCAM-1: 1.59-fold ± 0.12, vs. control). Additionally, expression of ER-stress markers was increased (e.g., GRP78; 1.32-fold ± 0.04 vs. control, p&amp;lt;0.01) (Fig.1). In contrast, VKORC1 downregulation significantly promoted proliferation (EdU signal: 3.9 ± 1.7 vs. control, p&amp;lt;0.01) as well as viability (alamarBlue® absorbance: 1.07 ± 0.08 vs. control, p=0.04), and decreased ROS (0.88 ± 0.17 vs. control, p=0.03). Pro-inflammatory and ER-stress proteins were either unaltered or decreased after VKORC1 knockdown (e.g., GRP78: 0.89-fold, VCAM-1: 0.68-fold) (Fig.2). To further elucidate these findings, we will perform overexpression experiments and stable knockdown of the VKOR-enzymes. Conclusion VKORC1 and its isoenzyme VKORC1L1 exhibit divergent effects on endothelial cell inflammation. Further studies are warranted to shed light on the regulation of the enzymes to improve our understanding regarding vascular side effects of VKA treatment and beneficial effects of vitamin K supplementation.

The endoplasmic reticulum (ER) chaperone GRP78 is secreted during ER Stress and alleviates endothelial cell inflammation

Abstract Introduction Glucose-Regulated Protein 78kD (GRP78) is a chaperone and the main regulator of the ER-stress response which is triggered by a variety of conditions that disturb folding of proteins in the ER. Upon ER Stress, GRP78 activates the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. Recently, extracellular secretion of GRP78 was described. However, the pathophysiological relevance of secreted GRP78 in atherosclerosis and endothelial cell inflammation remains to be elucidated. Aim of this study is to investigate the role of GRP78 secretion in endothelial cells. Methods and Results First, we sought to investigate if vascular cells secrete GRP78 during ER Stress. Human coronary artery endothelial cells (HCAEC) were treated with the ER stress inductor tunicamycin for up to 48h. After ER Stress induction, Western Blot and ELISA experiments detected an increased intracellular GRP78 expression. Intriguingly, prolonged ER Stress also promoted extracellular secretion of GRP78. Unbiased proteomic analysis of the HCAEC secretome confirmed that after ER-Stress induction, GRP78 is one of the most highly upregulated extracellular proteins (2.43-fold). Co-incubation with Brefeldin A, an inhibitor of ER-Golgi protein transport, abolished extracellular secretion (Fig.1). Hence, ER-Stress-induced GRP78 secretion is an actively regulated process. Next, the effect of GRP78 containing conditioned medium (CM) on HCAEC was analyzed. For control, HCAEC were co-incubated with BFA, or GRP78-knockdown was performed by siRNA. Treatment with GRP78 containing CM decreased GRP78 mRNA expression in target cells (0.35-fold vs. control [+BFA], p&amp;lt;0.0001). Furthermore, it increased viability ( BFA: 93.0 % vs. 83%, p=0.002; GRP78-siRNA: 94% vs. 85%, p=0.01) and decreased the rate of apoptosis (e.g. BFA: 1.7-fold vs. 5.1, p=0.02). Moreover, expression of markers of vascular inflammation and ER Stress (e.g., NF-κB and CHOP) were decreased when compared to CM without GRP78 (Fig.2). Furthermore, increased H2O2-generation was measured (BFA: 1.4-fold, p&amp;gt;0.001, GRP78-siRNA:1.3-fold, p=0.004) (Fig. 2). To confirm that the beneficial effects of the CM are in fact caused by GRP78, we treated HCAEC with recombinant GRP78 and observed an increased cell viability in a dose-dependent manner (1000 ng/ml: p=0.02 vs. control). CRIPTO is a membrane-bound co-receptor for growth factors and was previously linked to GRP78-signalling. siRNA-Knockdown of CRIPTO reduces viability and leads to cell apoptosis, irrespective of GRP78-treatment. Thus, GRP78-mediated effects may be mediated by CRIPTO. Conclusion Endothelial ER Stress promotes GRP78 secretion. Presence of GRP78 in conditioned medium ameliorates subsequent ER Stress and endothelial inflammation, which play a critical role in atherogenesis. Further investigations are important to shed light on the mechanism of release and the effect on target cells.

Abstract 13664: Relationship Between Vascular Inflammation Assessed by 18FDG-PET/CT and Coronary Calcification in Patients With Lung Cancer

Background: As the prognosis of lung cancer (LK) has improved over the years, atherosclerotic cardiovascular disease may affect the prognosis of LK. Previous studies have shown that vascular inflammation assessed by 18FDG-PET/CT and coronary artery calcification (CAC) assessed by chest CT can predict cardiovascular events. Objective: This study aimed to evaluate the relationship between vascular inflammation on 18FDG-PET/CT and CAC in patients with LK. Methods: Ninety-nine patients with LK who underwent both chest CT and 18FDG-PET/CT were included in this study. Vascular inflammation was assessed by 18FDG-PET/CT. Target-to-background ratio (TBR) was measured in 8 major arteries and was used as a marker of vascular inflammation. Agatston score was measured using chest CT images and was used as a marker of CAC. Results: The mean age was 70 years old (61 male). The median TBR was 1.39 (IQR: 1.33-1.43). Using a median value of TBR, patients were divided into 2 groups, high TBR group (≧1.39, n=50) and the low TBR group (&lt;1.39, n=49). High TBR group had more male gender (72% vs. 51%, p=0.03), was significantly older (71 (67-74)vs. 62(57-70)years, p&lt;0.001), and had diabetes (p=0.03). In contrast, the history of hypertension (p=0.993), dyslipidemia (p=0.622) and smoking(p=0.113) were similar between the groups. Agatston score was significantly higher in the high TBR group than in the low TBR group (168±338 vs. 56±97, p=0.005). Conclusion: Patients with lung cancer patients with high vascular inflammation had significantly higher Agatston score, suggesting an association between vascular inflammation and advanced coronary atherosclerosis. The impact of vascular inflammation and/or coronary calcification on the prognosis of LK needs further investigation.

FRI107 Ketogenic Diet Prevents Development Of Atherosclerotic Plaques In Apolipoprotein E Knockout Mice

Abstract Disclosure: V. Marzolla: None. A. Armani: None. C. Mammi: None. S. Gorini: None. E. Camajani: None. M. Caprio: None. Higher aldosterone (aldo) levels are associated with increased risk of cardiovascular ischemic events and mortality. It has been demonstrated that aldo accelerates the development of atherosclerosis in apolipoprotein E knockout mice (ApoE KO). Ketogenic diet (KD) positively impacts several cardiovascular risk factors, yet its effect on atherosclerosis is elusive. We hypothesize that KD protects from development of atherosclerotic plaques in ApoE KO mice, a murine model of atherosclerosis. Eight-week-old male ApoE KO mice were fed a KD (90,5% Kcal from fat, 0.4% Kcal from carbohydrate, 9.1% Kcal from protein) or a moderate high fat die (HFD) (42% Kcal from fat, 42.7% Kcal from carbohydrate, 15.2% Kcal from protein) and treated with aldosterone (aldo, 6 μg/mouse per day) or vehicle through osmotic mini-pumps. Cholesterol content was comparable in KD and HFD. After 4 weeks of treatment, in all experimental groups, intraperitoneal glucose tolerance test was performed, and peripheral blood samples were collected. We analysed cryosections of embedded aortic root to quantify the atherosclerotic plaque size, lipid and collagen content. We assessed vascular inflammation in speciments of thoracic aorta by analysing pro-inflammatory (ICAM-1, VCAM-1, IL-6, TNF-α, MCP-1) and anti-inflammatory (Arg-1, RETNLA, CCL5) genes. In ApoE KO mice treated with aldo, KD determined a significant improvement in glucose tolerance, compared to mice fed a HFD, without any significant effect on body weight. Beta-hydroxybutyrate levels were always significantly higher in KD-mice than in AD-mice, confirming nutritional ketosis in KD-mice. Analysis of aortic root showed that aldo treatment determined a significant increase in atherosclerotic plaque size and lipid content in HFD-mice. Such effects were significantly reduced in KD-mice, suggesting a favorable impact of ketosis in preventing atherosclerosis development. Plaque fibrosis did not differ among treatment groups. Finally, we observed a significant reduction in vascular inflammatory markers in KD-mice, when compared to HFD-mice. In particular, KD determined a significant reduction in gene expression of pro-inflammatory markers (ICAM-1, VCAM-1, IL-6, TNF-α, MCP-1) with the concomitant up-regulation of anti-inflammatory markers (Arg-1, RETNLA, CCL5), compared to HFD. The study suggests KD as a potential non-pharmacological approach to prevent the development of atherosclerotic disease in subjects with high cardiovascular risk. Presentation: Friday, June 16, 2023

Immunoliposomes for detection of rupture-prone intracranial aneurysms

BackgroundIt is estimated that significant (3.2%) of population carries intracranial aneurysm (IA). An increasing number of imaging studies have caused that the chance of finding an incidental aneurysm is becoming more common. Since IA rupture causes subarachnoidal hemorrhage (SAH) and have significant mortality and morbidity prophylactic treatment should be considered when IA is detected. The benefit and risk of treatment of IA is based on epidemiological estimate which takes account patient and aneurysm characteristics. However we know that aneurysm rupture is biological process where inflammation of aneurysm wall is actively leading to degeneration of aneurysm wall and finally weakens it until it bursts. Until now, there have not been imaging method to detect inflammatory process of aneurysm wallMethodsWe created targeting immunoliposome for use in the imaging of aneurysm. Immunoliposome comprises antibodies against at least one vascular inflammatory marker associated with aneurysm inflammation and a label and/or a contrast agent.ResultsHistological analysis of IAs where immunoliposome comprises antibodies against vascular inflammation with a label shows promising results for selectively detecting aneurysms inflammation. In magnetic resonance imaging (MRI) we were able to detect immunoliposomes carrying gadolinium.ConclusionOur work opens a new avenue for using contrast labeled immunoliposomes for detecting rupture-prone aneurysms. Immunoliposomes can cary gadolinium and selectively bind to inflammatory section of aneurysm that can be detected with MRI. Further research is needed to develop immunoliposomes to be used with MRI in humans to target treatment to those patients who benefit from it the most.

TGR5 supresses cGAS/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy

Diabetic retinopathy (DR) is a serious and relatively under-recognized complication of diabetes. Müller glial cells extend throughout the retina and play vital roles in maintaining retinal homeostasis. Previous studies have demonstrated that TGR5, a member of the bile acid-activated GPCR family, could ameliorate DR. However, the role of TGR5 in regulating Müller cell function and the underlying mechanism remains to be ascertained. To address this, high glucose (HG)-treated human Müller cells and streptozotocin-treated Sprague-Dawley rats were used in the study. The IP3R1-GRP75-VDAC1 axis and mitochondrial function were assessed after TGR5 ablation or agonism. Cytosolic mitochondrial DNA (mtDNA)-mediated cGAS-STING activation was performed. The key markers of retinal vascular leakage, apoptosis, and inflammation were examined. We found that mitochondrial Ca2+ overload and mitochondrial dysfunction were alleviated by TGR5 agonist. Mechanically, TGR5 blocked the IP3R1-GRP75-VDAC1 axis mediated Ca2+ efflux from the endoplasmic reticulum into mitochondria under diabetic condition. Mitochondrial Ca2+ overload led to the opening of the mitochondrial permeability transition pore and the release of mitochondrial DNA (mtDNA) into the cytosol. Cytoplasmic mtDNA bound to cGAS and upregulated 2’3’ cyclic GMP-AMP. Consequently, STING-mediated inflammatory responses were activated. TGR5 agonist prevented retinal injury, whereas knockdown of TGR5 exacerbated retinal damage in DR rats, which was rescued by the STING inhibitor. Based on the above results, we propose that TGR5 might be a novel therapeutic target for the treatment of DR.

Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear. Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND. Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls). Median age was 53 years, median CD4 count, and duration of HIV infection were 505 cells/μl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals (p<0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 (p < 0.01) and vascular disease (p = 0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models (p < 0.01). Furthermore, plasma VCAM-1 correlated with NFL (r = 0.29, p = 0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations. Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.

Sex differences in cardiometabolic biomarkers during the pre-diabetes stage

Using two large prospective epidemiological studies in the U.S., we examined biomarkers that reflect sex-specific pathophysiological pathways to cardiovascular complications among people with pre-diabetes. Women with pre-diabetes exhibited higher levels of adipokines, while men had lower eGFR. Sex differences in lipoproteins and vascular inflammatory markers during pre-diabetes indicate sex-specific lipoprotein and inflammatory mechanisms to cardiovascular complications.

Glycyrrhizic Acid Inhibits High-Mobility Group Box-1 and Homocysteine-Induced Vascular Dysfunction.

Hyperhomocysteinemia (HHcy) worsens cardiovascular outcomes by impairing vascular function and promoting chronic inflammation via release of danger-associated molecular patterns, such as high-mobility group box-1 (HMGB-1). Elevated levels of HMGB-1 have recently been reported in patients with HHcy. Therefore, targeting HMGB-1 may be a potential therapy to improve HHcy-induced cardiovascular pathologies. This study aimed to further elucidate HMGB-1's role during acute HHcy and HHcy-induced atherogenesis and to determine if inhibiting HMGB-1 with glycyrrhizic acid (Glyz) improved vascular function. Male New Zealand White rabbits (n = 25) were placed on either a standard control chow (CD; n = 15) or atherogenic diet (AD; n = 10) for 4 weeks. Rabbit serum and Krebs taken from organ bath studies were collected to quantify HMGB-1 levels. Isometric tension analysis was performed on abdominal aorta (AA) rings from CD and AD rabbits. Rings were incubated with homocysteine (Hcy) [3 mM] for 60 min to induce acute HHcy or rhHMGB-1 [100 nM]. Vascular function was assessed by relaxation to cumulative doses of acetylcholine. Markers of vascular dysfunction and inflammation were quantified in the endothelium, media, and adventitia of AA rings. HMGB-1 was significantly upregulated in serum (p < 0.0001) and Krebs (p < 0.0001) after Hcy exposure or an AD. Incubation with Hcy (p < 0.0001) or rhHMGB-1 (p < 0.0001) and an AD (p < 0.0001) significantly reduced relaxation to acetylcholine, which was markedly improved by Glyz. HMGB-1 expression was elevated (p < 0.0001) after Hcy exposure and AD (p < 0.0001) and was normalized after Glyz treatment. Moreover, markers of vascular function, cell stress and inflammation were also reduced after Glyz. These results demonstrate that HMGB-1 has a central role during HHcy-induced vascular dysfunction and inhibiting it with Glyz could be a potential treatment option for cardiovascular diseases.

C-Reactive Protein Level and the Genetic Variant rs1130864 in the CRP Gene as Prognostic Factors for 10-Year Cardiovascular Outcome.

Cardiovascular disease (CVD) is the primary cause of premature death and disability worldwide. There is extensive evidence that inflammation represents an important pathogenetic mechanism in the development and prognosis of CVD. C-reactive protein (CRP) is a potential marker of vascular inflammation and plays a direct role in CVD by promoting vascular inflammation. The objective of this study (ClinTrials.gov identifier: NCT01045070) was to assess the prognostic impact of CRP protein levels and genetic variants of CRP gene events on cardiovascular (CV) outcome (10-year follow-up) in patients suffering from CVD. CVD patients were prospectively included in this study (n = 1002) and followed up (10 years) regarding combined CV endpoint (CV death, death from stroke, myocardial infarction (MI), and stroke/transient ischemic attack (TIA)). CRP protein level (particle-enhanced immunological turbidity test) and genetic variants (rs1130864, rs1417938, rs1800947, rs3093077; polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) after DNA extraction from EDTA-blood) were evaluated. In survival analyses, increased CRP protein levels of ≥5 mg/L (log-rank test: p < 0.001, Cox regression: p = 0.002, hazard ratio = 1.49) and CT + TT genotype of rs1130864 (log-rank test: p = 0.041; Cox regression: p = 0.103, hazard ratio = 1.21) were associated with a weaker CV prognosis considering combined CV endpoint. Elevated CRP level and genetic variant (rs1130864) were proven to provide prognostic value for adverse outcome in CVD patients within the 10-year follow-up period.

1225-P: Biomarkers in Prediabetes Reflecting Sex Varying Pathways of Cardiovascular Risk

Background: Women with diabetes (DM) had higher cardiovascular risk than men, partly due to women’s higher cardiometabolic risk factors before DM. We compared sex differences in biomarkers that reflect distinct pathophysiological pathways in prediabetes (PreDM). Method: We conducted a cross-sectional analysis of similarly designed Atherosclerosis Risk in Communities Study and the Jackson Heart Study. We used multivariable linear regressions for the associations between sex and biomarkers (log(x)) representative of inflammation, cardiac injury/stress, lipoprotein, adipokine, kidney function, and glycemia adjusted for age, race, BMI, blood pressure, total cholesterol, smoking, hypertensive meds, and statins in CVD-free individuals with PreDM. We evaluated the effect modification of menopause and validated results in those who progressed into DM in follow-up. False discovery rate adjusted multiple comparisons. Results: In 5765 people with PreDM at baseline, the mean age was 54 y, 47% women, and 35% non-Hispanic Blacks. Inflammatory c-reactive protein (β coefficient 0.3 P=5×10-51), fibrinogen (β 0.2 P=3×10-12), and lymphocyte count (β 0.2 P=7×10-8), and cardiac NT-proBNT (β 0.6 P=1×10-104) were higher in women than men with PreDM. Lipoprotein(a) (β 0.2 P=1×10-10) and apolipoproteins A1 (Apo A1) (β 0.6 P=5 x 10-115), and adipokines, leptin (β 1.1 P=3×10-112) and adiponectin (β 0.6 P=6×10-16) were higher in women. Men with PreDM had higher random urinary creatinine (β -0.6 P=2×10-61) and reduced eGFR (β 0.3 P=5×10-29). They also had higher inflammatory homocysteine (β -0.5 P=2×10-12), triglycerides (β -0.2 P&amp;lt;.0001), and Apo B (β -0.1 P&amp;lt;.0001). Fructosamine, glycated albumin, and HbA1c did not differ by sex in PreDM. Menopause modifies sex differences in LDL-c, Apo B, and fibrinogen. Results were generally unchanged in people who later became DM. Conclusion: Overall, in PreDM, women had higher vascular inflammatory markers and adipokines, while men had higher kidney dysfunction markers. Disclosure Y.Yoshida: None. Z.Chen: None. C.Li: None. V.Fonseca: Consultant; Abbott, Corcept Therapeutics, Eli Lilly and Company, Other Relationship; BRAVO4HEALTH, LLC, Research Support; Fractyl Health, Inc., Stock/Shareholder; Amgen Inc. F.Mauvais-jarvis: None. Funding National Institutes of Health (K12HD043451)