Levels Of Soluble Adhesion Molecules Research Articles

Time-restricted feeding does not improve nephropathy in humanized sickle cell disease mice

Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by a point mutation in the hemoglobin gene. This substitution results in a “sickling” of red blood cells and subsequent vascular and organ damage. Current treatments, while increasing the lifespan of sickle cell patients, has resulted in a higher prevalence of chronic complications like SCD nephropathy. Our group has previously shown that time-restricted feeding (TRF) in chronic high fat fed mice reduces kidney damage. Given the increased kidney damage in SCD, we hypothesize that TRF in humanized SCD mice will attenuate sickle cell nephropathy. To test this hypothesis, we studied 18-22-week-old male SCD mice. Mice underwent 3 weeks of TRF, only having access to food during the active, dark period (Zeitgeber Time (ZT) 12 to 24). The control group had access to food ad libitum (ad-lib). At the end of the 3 weeks, at 21-25 week old ages, 12 hour urine was collected in metabolic cages as well as kidneys and plasma collection at ZT3 (inactive period). Excretion of urinary kidney damage markers (albumin and NGAL-1) showed no difference between TRF and ad-lib in both the active and inactive collection periods. Urinary excretion of endothelin-1 is known to be upregulated in SCD patients; however, TRF did not change this marker in SCD mice. TRF did not change plasma levels of cytokines or soluble adhesion molecules. Histological analysis of kidneys was conducted as an additional marker of kidney damage. We analyzed iron levels in the kidney with Prussian blue staining as well as fibrosis with Masson’s trichrome. TRF did not change kidney iron accumulation or kidney fibrosis. Immunohistochemical staining for CD3+ T cells did not show a difference in glomerular T cell infiltration in the TRF group compared to the ad-lib group. In conclusion, TRF does not appear to have an effect on renal inflammation or kidney function in SCD mice, but future studies need to be completed. R01 DK134562. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders

BackgroundEndothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. MethodsThe study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. ResultsThe total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. ConclusionsIn our study, patients with schizophrenia – including the drug-naïve – have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk.

Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10-18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10-5; 4PY: rho = 0.18, P = 1.1 × 10-8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.

The associations of markers of endothelial dysfunction with hip fracture risk.

Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. Participants for this study were 2792 individuals (mean age 78.6years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

Increased Circulating Soluble Junctional Adhesion Molecules in Systemic Sclerosis: Association with Peripheral Microvascular Impairment

Systemic sclerosis (SSc, scleroderma) is a severe disease characterized by peripheral microcirculation abnormalities manifesting with Raynaud's phenomenon, nailfold videocapillaroscopic (NVC) changes, and even ischemic digital ulcers (DUs) that are often refractory to treatments. In the wake of previously described associations between the circulating levels of soluble junctional adhesion molecules (sJAMs) and SSc clinical features, here, we measured sJAM-A and sJAM-C levels by enzyme-linked immunosorbent assay in serum samples from a large case series of 110 SSc patients and 85 healthy controls, focusing on their possible association with peripheral vascular clinical features and their potential as biomarkers that are either diagnostic or mirror SSc-related microvasculopathy severity. Our data demonstrated that serum sJAM-A and sJAM-C are significantly increased in patients with SSc vs. healthy controls, especially in those featuring early/active NVC patterns and the presence of ischemic DUs. Moreover, circulating sJAM-C levels showed good diagnostic accuracy in discriminating between patients and controls, as assessed by receiver operator characteristics curve analysis. Finally, logistic regression revealed that, when comparing sJAM-A to sJAM-C, the latter might be better suited as a biomarker for SSc-related DUs. Our promising findings provide the necessary groundwork for longitudinal follow-up analyses of SSc patients aiming to assess whether circulating sJAM-C levels might be predictive for the development of new DUs, as well as DU recurrence and/or refractoriness to targeted therapies.

The role of endothelial protection in the treatment of patients with arterial hypertension: the effectiveness of quercetin

The article presents the results of a clinical study of the effectiveness of the cytoprotective drug quercetin as a part of combined antihypertensive therapy on indices of endothelial function and daily blood pressure profile. The aim of the study. To conduct a comparative assessment of the dynamics of indices in 24-hour blood pressure monitoring (BPM) and cytokine levels in patients with hypertension, depending on using quercetin in treatment.Materials and methods. 120 patients with stage II hypertension of 2–3 degrees (66 female and 54 male) were examined. Patients were divided into 2 groups: Group I (study) – 58 patients who took quercetin (Corvitin®) in addition to basic therapy, mean age 57.87±13.6 years; II group (comparison) – 62 patients who underwent only basic antihypertensive therapy (Ramipril/Amlodipine), mean age 59.09±12.47 years. The results. During the administration of quercetin along with the standard basic therapy with the combination of Ramipril/Amlodipine in patients with stage II hypertension of 2-3 degrees of severity, more pronounced significant positive changes in the major indices of 24-hour BPM were observed, an increase in the ratio of people with a “dipper” profile due to a decrease in the number of patients with an insufficient reduction in nocturnal BP, an excessive drop in nocturnal BP or its persistent increase. The additional administration of quercetin contributes to the more effective correction of endothelial dysfunction indices: it significantly reduces the levels of soluble vascular cell adhesion molecules (s-VCAM), and soluble intercellular adhesion molecules 1 (s-ICAM-1), ET-1, IL-1, IL-6, TNF-a. During the administration of basic therapy, changes in IL-1 and ET-1 levels were less pronounced and insignificant. Correlation analysis shows the close relationship between a decrease in the main indices of 24-hour BPM and a decrease in the concentration of the cytokines, which characterize the state of endothelial dysfunction and systemic inflammation.Conclusion. The use of quercetin reliably reduces the levels of cytokines, which ensures a reduction in the manifestations of ED and contributes to better control of all blood pressure indices and normalization of the daily profile of blood pressure.

P302 ENDOTHELIALITIS AS A POSSIBLE CAUSE OF MYOCARDIAL INJURY DURING COVID–19 INFECTION

A 53–year–old woman was admitted for chest pain for over two weeks, fever, dry cough, fatigue and myalgia. Chest pain increased in supine position and inspiration. Nasopharyngeal swab was positive for SARS–CoV–2 RT–PCR assay. Admission ECG displayed mild ST–segment elevation (0,5 mm) in inferolateral leads and echocardiogram showed normal left ventricular volume, mildly decreased left ventricular EF (52%) and no regional wall motion abnormalities. Blood tests exhibited elevated values of high–sensitivity troponin I (818 pg/mL), proBNP (19.190 pg/mL), CRP (42 mg/dL), D–Dimer test (1090 ng/mL) and WBC (13000/uL, N 89%, L 7%). IL–6 resulted slightly increased (18 ng/mL). ECG after 24 hours showed T wave inversion in inferolateral leads. Coronary CT angiography revealed normal epicardial arteries. A new echocardiogram, after five days, showed infero–basal hypokinesia, improved global EF (57%) and minimal pericardial effusion. Aspirin and fondaparinoux were started. Myopericarditis was suspected and high dose steroids were administered. After a few days, symptoms improved and ECG, echocardiographic abnormalities and troponin levels were normalized. At 6 weeks follow–up the patient was asymptomatic, ECG and echocardiogram were both normal. Instead cardiac MRI showed signs of endothelial injury: presence of interstitial oedema in the inferoapical and anteroseptal wall (STIR–T2–weighted), without late gadolinium enhancement. We measured blood levels of endothelial dysfunction markers: soluble ICAM–1, VCAM–1 and von Willebrand factor (vWF). They all resulted elevated as compared to a laboratory pool of normal serum (535 ng/ml, 265 ng/ml, and 1659 ng/ml, respectively). Our case was suggestive of myopericarditis related to Sars–Cov–2, but echocardiogram and MRI did not show signs of myocarditis permanent damage. However MRI showed interstitial oedema and hyperemia, typical signs of endothelial injury. Moreover we found high levels of soluble endothelial adhesion molecules, vWF, ICAM–1 and VCAM–1, likely expression of the microcirculatory endothelial dysfunction due to myocardial endothelialitis.In conclusion, our case report suggests that, in COVID–19, acute myocardial injury associated with clinical and investigational signs of myocarditis can be due to myocardial endothelialitis rather than true myocarditis and that an early management with anti–inflammatory drugs (steroids) can be particularly beneficial in patients with unexplained elevated cardiac troponin.

Comparison of protective effects of alprostadil with Salvia miltiorrhiza against myocardial ischemia-reperfusion injury in rats

ObjectivesOur study aimed to investigate the effects of alprostadil and Salvia miltiorrhiza extract on myocardial ischemia-reperfusion injury (IRI) and related underlying molecular mechanisms. MethodsA myocardial IRI model was established in Wistar rats via surgical ligation of the left anterior descending coronary artery followed by loosening of the occlusion. The rats were divided into four groups: saline, sham, alprostadil, and S. miltiorrhiza. Rats in the saline and sham groups were injected with normal saline by tail vein once daily for 10 consecutive days. Rats in the S. miltiorrhiza and alprostadil groups were injected with S. miltiorrhiza extract (20 μg/kg) or alprostadil. Histological differences in myocardial tissues between rats in the sham group and in the myocardial IRI model were observed by hematoxylin and eosin staining. India ink perfusion was used to quantify the number of capillary microvessels. Real-time quantitative reverse transcription polymerase chain reaction was used to determine serum expression levels of soluble intercellular adhesion molecule (sICAM), soluble vascular adhesion molecule (sVCAM), CD11b and CD18. ResultsThe alprostadil and S. miltiorrhiza groups had significantly higher numbers of microvessels than the saline group. Serum sICAM and sVCAM expression was significantly reduced in the alprostadil and S. miltiorrhiza groups. Meanwhile, sICAM and sVCAM in the alprostadil group were markedly lower than in the S. miltiorrhiza group. Moreover, the alprostadil group had markedly lower mRNA expression of CD11b and CD18, which were clearly lower than in the S. miltiorrhiza group. ConclusionAlprostadil may have cardioprotective effects for myocardial IRI, with down-regulated expression of sICAM, sVCAM, CD11b, and CD18.

The Predictive Role of Serum Levels of Soluble Cell Adhesion Molecules (sCAMs) in the Therapy of Advanced Breast Cancer-A Single-Centre Study.

Background and Objectives: Soluble cell adhesion molecules (sCAMs) play a significant role in the metastatic potential of breast cancer (BC). They might block lymphocytes and promote angiogenesis and migration of cancer cells. We assessed the usefulness of sCAMs in the prognosis and monitoring of the progression of advanced BC. Materials and Methods: We assessed soluble E-selectin, P-selectin, VCAM-1, ICAM-1, EpCAM, IL-6Ra, TNF-R1, and TNF-R2 in 39 women with aBC. Blood samples were obtained at the beginning of the treatment and after 2 months. Results: The median progression-free survival (PFS) was 9 months, and overall survival (OS) was 27 months. The higher levels of sICAM-1 (HR = 2.60, p = 0.06) and lower levels of sEpCAM (HR = 2.72, p < 0.05) were associated with faster progression of aBC. High levels of sEpCAM through the follow-up period were significantly associated with a lower risk of progression (HR = 0.40, p < 0.01). We found the independent predictive value of higher than median sICAM-1 levels for PFS (HR = 2.07, p = 0.08) and of sVCAM-1 levels for OS (HR = 2.59, p < 0.05). Conclusions: Our data support the predictive value of sICAM-1 and sVCAM-1 and suggest that they could become markers for tailoring new therapies in aBC. sEpCAM level could be used as an early indicator of response to the therapy.

Estimation of Vascular Cell Adhesion Molecule 1 (VCAM-1) Levels In Type 1 Diabetic Mellitus Patients

High glucose levels in patients with diabetes are associated with increased plasma levels of soluble adhesion molecules. They could explain that the patients with diabetes mellitus will require the development of premature atherosclerosis related to hyperglycemia or hyperinsulinemia and that it not only affects vascular endothelium but also contributes to the development of microvascular complications. This study aimed to evaluate the serum concentration of VCAM-1 in type 1 diabetes mellitus patients with and without cardiovascular disease. Also, investigation the association of insulin levels, duration of diabetes, and HbA1C with VCAM-1. Include in this study a total of 60 types 1 diabetic patient. According to characteristic laboratory investigations and electrocardiogram (ECG), they were subdivided into two groups (G1) 30 T1DM patients without cardiovascular disease and (G2) 30 T1DM patients with cardiovascular disease in addition to 30 healthy subjects as a control group (G3). All subjects measured the levels of fasting blood glucose FBG, glycated hemoglobin HbA1c, and insulin levels, and VCAM-1 were also determined by ELISA technique. This study shows a highly significant difference in the average diabetic profile between G1 and G2 compared to the control group and found that VCAM-1 level was significantly higher among diabetic patients than the control group. Also, there was a significant negative correlation of VCAM-1 with the levels of FBG, HbA1c in diabetic patients G1 and G2. While insulin had a positive correlation in G1 but correlated negatively in G2

Elevated Serum Levels of Progranulin and Soluble Vascular Cell Adhesion Molecule-1 in Patients with COVID-19.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with the angiocentric inflammation and angiogenesis, yet the molecules involved in this process remain to be determined.MethodsWe did a cross-sectional study of a cohort of patients with COVID-19 in Zunyi, China between February 1 and March 30, 2020. Serum concentrations of PGRN were determined by enzyme-linked immunosorbent assay in patients with COVID-19 at hospital admission and at discharge. In parallel, the serum levels of soluble adhesion molecules, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), P-selectin (sP-selectin), and E-selectin (sE-selectin) were assayed by a human adhesion molecule multiplex kit. The association between serum PGRN levels and other laboratory test results was analyzed by Spearman correlation analysis.ResultsAt baseline, the median serum PGRN levels in patients with COVID-19 were 94.8 ng/mL [interquartile range (IQR): 66.6–119.6 ng/mL], which was significantly elevated compared with those in healthy controls (46.3 ng/mL, IQR: 41.8–55.6 ng/mL). Moreover, the median serum sVCAM-1 levels were significantly higher in COVID-19 patients (1396.0 ng/mL, IQR: 1019.1–1774.8 ng/mL) than those in healthy controls (612.4 ng/mL, IQR: 466.4–689.3 ng/mL). However, the levels of sICAM-1, sP-selectin, and sE-selectin were not significantly elevated in patients with COVID-19 when compared to healthy controls. Further analysis showed that serum PGRN levels were significantly positively associated with sVCAM-1 (r= 0.675, P= 0.008) and inversely with sICAM-1 (r= −0.609, P= 0.021) and aspartate aminotransferase levels (r= −0.560, P= 0.037) in patients with COVID-19 at hospital admission. In COVID-19 patients, serum PGRN and sVCAM-1 levels fell significantly after successful treatment.ConclusionThe present study demonstrates elevated serum PGRN and sVCAM-1 levels in patients with COVID-19, which may provide clues as to the mechanisms underlying the pathogenesis of COVID-19. Further studies are warranted to evaluate the potential of PGRN and sVCAM-1 as biomarkers and investigate their role in the pathogenesis of COVID-19.

Effect of Cannabinoid 2 Receptor Modulation on the Peripheral Immune Response in Central Nervous System Injury-Induced Immunodeficiency Syndrome.

Introduction: Acute central nervous system (CNS) injury, such as stroke, spinal cord injury, or traumatic brain injury can result in dysregulated immune response, and the condition is known as CNS injury-induced immunodeficiency syndrome (CIDS). The endocannabinoid system is an important homeostatic regulator in the CNS and immune system. Activation of cannabinoid 2 receptors (CB2R) on immune cells has been reported to dampen inflammation, suggesting a potential role of CB2R in the peripheral immune response following CNS injury. In this study, we have investigated the effect of CB2R modulation on the peripheral immune response during CIDS. Materials and Methods: Experimental CNS injury was induced in C57BL/6 mice through intracerebral injection of the vasopressor peptide, endothelin-1. A selective CB2R agonist (HU308) was used as an early treatment before the onset of CIDS and AM630, a selective CB2R antagonist, was administered as a later-phase therapy to combat the systemic immunodeficiency following the CNS injury. The peripheral immune response to endotoxin was studied 24 h after the CNS injury using intravital microscopy to examine leukocyte activation within the intestinal microcirculation in mice. Brain infarct size, and plasma levels of cytokines and soluble adhesion molecules were measured as additional parameters for the assessment of treatment outcomes. Results: Our results showed that early CB2R activation with HU308 reduced brain injury size and restored leukocyte response to endotoxin in the peripheral microcirculation. Late CB2R inhibition with AM630 also improved the peripheral leukocyte response to endotoxin and did not exacerbate the extent of brain injury. Discussion: CB2R activation has the potential to mitigate CNS injury as an early treatment by limiting neuroinflammation and preventing the development of CIDS. At the later stage with already-established CIDS, treatment may require dampening CB2R activation to improve the patient's outcome.

Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis.

Background: Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS).Objectives: This study aimed to evaluate the combined contribution of the hemostasis inhibitor protein C (PC) and chemokine C-C motif ligand 18 (CCL18) levels to brain atrophy in MS and to identify disease-relevant correlations among circulating levels of hemostasis inhibitors, chemokines, and adhesion molecules, particularly in CMB occurrence in MS.Methods: Plasma levels of hemostasis inhibitors (ADAMTS13, PC, and PAI1), CCL18, and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138 MS patients [85 relapsing-remitting (RR-MS) and 53 progressive (P-MS)] and 42 healthy individuals (HI) who underwent 3-T MRI exams. Association of protein levels with MRI outcomes was performed by regression analysis. Correlations among protein levels were assessed by partial correlation and Pearson's correlation.Results: In all patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including the brain parenchyma (p = 0.002), gray matter (p < 0.001), cortex (p = 0.001), deep gray matter (p = 0.001), and thalamus (p = 0.001). These associations were detectable in RR-MS but not in P-MS patients. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p = 0.03) and in the P-MS (p = 0.003). In the P-MS, higher CCL18 levels were also associated with lower volumes of the gray matter (p = 0.024), cortex (p = 0.043), deep gray matter (p = 0.029), and thalamus (p = 0.022). PC-CCL18 and CCL18-PAI1 levels were positively correlated in both MS and HI, PC–sVAP1 and PAI1–sVCAM1 only in MS, and PC–sICAM1 and PC–sNCAM only in HI. In MS patients with CMBs (n = 12), CCL18–PAI1 and PAI1–sVCAM1 levels were better correlated than those in MS patients without CMBs, and a novel ADAMTS13–sVAP1 level correlation (r = 0.78, p = 0.003) was observed.Conclusions: Differences between clinical phenotype groups in association of PC and CCL18 circulating levels with MRI outcomes might be related to different aspects of neurodegeneration. Disease-related pathway dysregulation is supported by several protein level correlation differences between MS patients and HI. The integrated analysis of plasma proteins and MRI measures provide evidence for new relationships among hemostasis, inflammation, and immunity pathways, relevant for MS and for the occurrence of CMBs.

Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease.

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5' GMP (cGMP) signaling plays a central role in regulation of diverse processes including smooth muscle relaxation, inflammation, and fibrosis. sGC is activated by the short-lived physiologic mediator NO. sGC stimulators are small-molecule compounds that directly bind to sGC to enhance NO-mediated cGMP signaling. Olinciguat, (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide, is a new sGC stimulator currently in Phase 2 clinical development. To understand the potential clinical utility of olinciguat, we studied its pharmacokinetics, tissue distribution, and pharmacologic effects in preclinical models. Olinciguat relaxed human vascular smooth muscle and was a potent inhibitor of vascular smooth muscle proliferation in vitro. These antiproliferative effects were potentiated by the phosphodiesterase 5 inhibitor tadalafil, which did not inhibit vascular smooth muscle proliferation on its own. Olinciguat was orally bioavailable and predominantly cleared by the liver in rats. In a rat whole body autoradiography study, olinciguat-derived radioactivity in most tissues was comparable to plasma levels, indicating a balanced distribution between vascular and extravascular compartments. Olinciguat was explored in rodent models to study its effects on the vasculature, the heart, the kidneys, metabolism, and inflammation. Olinciguat reduced blood pressure in normotensive and hypertensive rats. Olinciguat was cardioprotective in the Dahl rat salt-sensitive hypertensive heart failure model. In the rat ZSF1 model of diabetic nephropathy and metabolic syndrome, olinciguat was renoprotective and associated with lower circulating glucose, cholesterol, and triglycerides. In a mouse TNFα-induced inflammation model, olinciguat treatment was associated with lower levels of endothelial and leukocyte-derived soluble adhesion molecules. The pharmacological features of olinciguat suggest that it may have broad therapeutic potential and that it may be suited for diseases that have both vascular and extravascular pathologies.

Soluble Intercellular Adhesion Molecule- (sICAM-) 1, Thrombospondin-1, and Vinculin for the Identification of Septic Shock Patients Suffering from an Invasive Fungal Infection

Background. Nowadays, invasive fungal infections (IFI) are of increasing importance and associated with an increased mortality. However, reliable diagnostic tools for the identification of patients suffering from an IFI are rare and associated with relevant weaknesses.Methods. Within this secondary analysis of an observational clinical study, an innovative biomarker panel (consisting of 62 biomarkers in total) was screened for the identification of septic shock patients suffering from an IFI. Fungal growth in blood cultures, intraoperative swabs, andAspergillusspp. in deep respiratory tract specimens with accompanying pulmonary infiltrates were classified as infection, whereasCandidaspp. in the respiratory tract or in fluids from drainages were classified as colonization. Plasma samples of 50 septic shock patients at six predefined timepoints within a period of 28 days following the onset of septic shock were available.Results. In total, 11 out of the 50 patients (22%) were shown to suffer from an IFI, whereas 22 patients (44%) presented with a fungal colonization. Within the presented biomarker panel, plasma levels of soluble intercellular adhesion molecule- (sICAM-) 1, thrombospondin-1, and vinculin were shown to be the most promising. sICAM-1 was shown to be increased in patients with an IFI, whereas thrombospondin-1 and vinculin revealed decreased plasma levels as compared to colonized patients as well as patients without any fungal findings at any time.Conclusion. Plasmatic measurements of sICAM-1, thrombospondin-1, and vinculin may help to facilitate the diagnosis of an IFI in human septic shock and to identify patients with an increased risk for an IFI. This trial is registered withDRKS00005463.

Levels of soluble cell adhesion molecules in type 2 diabetes mellitus patients with macrovascular complications.

ObjectiveType 2 diabetes mellitus (T2DM) is a main risk factor for development of cardiovascular diseases (CVDs) and endothelial dysfunction. This study aimed to investigate serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), intercellular adhesion molecule 1 (sICAM-1), and endothelium selectin (sE-selectin) in T2DM patients with macrovascular complications.MethodsA cross-sectional study of 21 controls, 30 T2DM patients without CVDs, and 30 T2DM patients with CVDs was conducted. Serum levels of soluble adhesion molecules including sVCAM-1, sICAM-1, and sE-selectin were determined using ELISA.ResultsSerum levels of sVCAM-1, sICAM-1, and sE-selectin were higher in T2DM patients than in controls. Levels of serum sVCAM-1 were higher in T2DM patients with CVDs compared with T2DM patients without CVDs. In T2DM patients with CVDs, significant positive associations were observed between sVCAM-1, sICAM-1, and sE-selectin levels (r = 0.575, p = 0.001 and r = 0.378, p = 0.040).ConclusionsCirculating levels of soluble adhesion molecules were elevated in T2DM patients, regardless of whether the patients had cardiovascular complications. Only sVCAM-1 was considered a useful marker for the prediction of CVDs in T2DM patients.

Policosanol Attenuates Cholesterol Synthesis via AMPK Activation in Hypercholesterolemic Rats.

This study was carried out to investigate the effects of policosanol on high-fat and high-cholesterol diet-induced hypercholesterolemic rats to provide strong evidence in support of its hypocholesterolemic effect. The hypercholesterolemic rats showed elevations in liver weight, total triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol in serum; however, policosanol supplementation reduced these markers significantly. In addition, we found that policosanol supplementation stimulated an increase in fecal cholesterol and bile acid contents and deactivated 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase by AMP-activated protein kinase (AMPK) phosphorylation during high-fat and high-cholesterol-containing diet-induced development of hypercholesterolemia. Policosanol supplementation decreased ApoB levels and increased LDL-receptor expression, but it did not affect the hepatic ACAT2 level in livers from hypercholesterolemic rats. Moreover, supplementation with policosanol significantly decreased aortic wall thickness and levels of P-selectin and soluble vascular cell adhesion molecule (sVCAM-1) in serum. In conclusion, we suggest that policosanol supplementation induces antihypercholesterolemia by inhibiting cholesterol biosynthesis, LDL cholesterol uptake, and cholesterol excretion.

EP18.10: Maternal endothelium and risk of developing cardiovascular diseases

In Pakistan, It has been strongly suggested that women with hypertensive disorders of pregnancy are at risk of developing cardiovascular disorders. Our objective was to ascertain the persistence of endothelial activation in hypertensive pregnancies compared to women with normal pregnancies. Case control study design was chosen in two matched group. Endothelial activation was determined by the evaluation of adhesion molecules namely P-selectin, E-selectin, intercellular adhesion molecules-1 (ICAM-1) and vascular cellular adhesion molecules-1 (VCAM-1). In the first study, adhesion molecules were measured in 40 women with hypertensive pregnancies and in a matched control group with an uncomplicated pregnancy one month and three months after delivery. In the second study, adhesion molecules were measured in 40 patients with a history of HELLP syndrome several years after pregnancy and in 40 matched controls. Shortly after the delivery, increased levels of soluble adhesion molecules were found in women with hypertensive complications. However, women with uncomplicated pregnancy did not have any increase level of soluble adhesion molecules. Significant differences were still present, several years after delivery comparing levels of adhesion molecules in women with a history of HELLP syndrome with those found in control patients. An abnormal activation of endothelium was seen in hypertensive pregnancies. It has also been concluded that is abnormal activation of endothelium remains increased even after delivery which pre disposes the patient towards cardiovascular disorder. The risk of cardiovascular complications including ischemic heart diseases, chronic hypertension and stroke is more commonly seen in women experiencing HELLP syndrome.

Alteration in serum levels of ICAM-1 and P-, E- and L-selectins in seriously eye-injured long-term following sulfur-mustard exposure

IntroductionIn this study, the serum levels of soluble intercellular adhesion molecule 1 (ICAM-1), P-, E-, and L-selectins were investigated in seriously eye-injured patients exposed to sulfur mustard (SM). Material and methodsA total of 128 individuals with SM-induced serious eye injuries and 31 healthy male controls were included in this study. The serum concentration of soluble forms of adhesion molecules was measured by enzyme-linked immunosorbent assay (ELISA) method. ResultThe serum level of soluble ICAM-1 was significantly higher in the SM-exposed individuals with an abnormality in tear meniscus height, corneal verticillata, and pannus compared with SM-exposed individuals without these abnormalities. There were no significant differences in the level of all three measured selectins between the SM-exposed group and the control groups. SM-exposed individuals with corneal defect had a significantly higher level of soluble E-selectin than SM-exposed individuals without this abnormality. The serum level of soluble P-selectin in the SM-exposed group with limbal abnormality was significantly lower than that in the SM-exposed without this abnormality; also it was significantly higher in SM-exposed group with fundus abnormality compared to that in the control group or SM-exposed group without this abnormality. ConclusionThe changes in the levels of selectins and ICAM-1 in the SM-exposed group with various ocular abnormalities is a defense mechanism against the toxicity of SM. Further analysis is required to understand the molecular mechanisms of the relationship between adhesion molecules with ocular complications in SM-exposed individuals.

Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns

BackgroundInflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood.ObjectiveTo assess genetic...