Clinopodium chinense Attenuates Palmitic Acid-Induced Vascular Endothelial Inflammation and Insulin Resistance through TLR4-Mediated NF-κB and MAPK Pathways

2019 ◽  
Vol 47 (01) ◽  
pp. 97-117 ◽  
Author(s):  
Xiaoji Shi ◽  
Shanshan Wang ◽  
Huiling Luan ◽  
Dina Tuerhong ◽  
Yining Lin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Palmitic Acid ◽  
Vascular Endothelium ◽  
Interleukin 1 ◽  
No Production ◽  
Vascular Endothelial ◽  
Mapk Pathways

Elevated palmitic acid (PA) levels are associated with the development of inflammation, insulin resistance (IR) and endothelial dysfunction. Clinopodium chinense (Benth.) O. Kuntze has been shown to lower blood glucose and attenuate high glucose-induced vascular endothelial cells injury. In the present study we investigated the effects of ethyl acetate extract of C. chinense (CCE) on PA-induced inflammation and IR in the vascular endothelium and its molecular mechanism. We found that CCE significantly inhibited PA-induced toll-like receptor 4 (TLR4) expression in human umbilical vein endothelial cells (HUVECs). Consequently, this led to the inhibition of the following downstream adapted proteins myeloid differentiation primary response gene 88, Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-[Formula: see text] and TNF receptor-associated factor 6. Moreover, CCE inhibited the phosphorylation of Ikappa B kinase [Formula: see text], nuclear factor kappa-B (NF-[Formula: see text]B), c-Jun N-terminal kinase, extracellular regulated protein kinases, p38-mitogen-activated protein kinase (MAPK) and subsequently suppressed the release of tumor necrosis factor-[Formula: see text], interleukin-1[Formula: see text] (IL-1[Formula: see text]) and IL-6. CCE also inhibited IRS-1 serine phosphorylation and ameliorated insulin-mediated tyrosine phosphorylation of IRS-1. Moreover, CCE restored serine/threonine kinase and endothelial nitric oxide synthase (eNOS) activation and thus increased insulin-mediated nitric oxide (NO) production in PA-treated HUVECs. This led to reverse insulin mediated endothelium-dependent relaxation, eNOS phosphorylation and NO production in PA-treated rat thoracic aortas. These results suggest that CCE can significantly inhibit the inflammatory response and alleviate impaired insulin signaling in the vascular endothelium by suppressing TLR4-mediated NF-[Formula: see text]B and MAPK pathways. Therefore, CCE can be considered as a potential therapeutic candidate for endothelial dysfunction associated with IR and diabetes.

Abstract 398: Apolipoprotein CIII (apoCIII) Inhibits Insulin-dependent Endothelial Nitric Oxide Synthase (eNOS) Function In Endothelial Cells Through Protein Kinase C (PKC) βII

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Akio Kawakami ◽  
Mariko Tani ◽  
Mizuko Osaka ◽  
Frank M Sacks ◽  
Kentaro Shimokado ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Vascular Endothelium ◽  
Endothelial Nitric Oxide Synthase ◽  
No Production ◽  
Impaired Insulin ◽  
Insulin Dependent ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Objective Apolipoprotein (apo) CIII, a prominent component of atherogenic dyslipidemia, is elevated in patients with type2 diabetes and insulin resistance, and independently predicts cardiovascular disease (CVD). Endothelial dysfunction is an important component of the pathophysiology of atherosclerosis, and is associated with insulin resistance. We previously reported that apoCIII has a direct effect on vascular endothelium, activating endothelial cells to recruit monocytes through PKCβ and NF-κB-dependent mechanisms. In the present study, we investigated the effect of apoCIII on insulin-dependent endothelial nitric oxide synthase (eNOS) function in endothelial cells and in the aortas of C57BL/6J mice. Methods and Results ApoCIII treatment (100μg/ml, 30 minutes) inhibited insulin-induced ISR-1/phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells (HUVECs). Furthermore, apoCIII reduced insulin-stimulated eNOS activation and NO release into the media. ApoCIII induced PKCβII activation in HUVECs, resulting in IRS-1 phosphorylation at pSer 616 and ERK activation. Impaired insulin-stimulated eNOS activation and NO production were restored by PKCβ inhibitor and MEK1 inhibitor to a lesser extent. In addition, treatment of C57BL/6J mice with apoCIII resulted in impaired insulin-dependent activation of PI3K/Akt/eNOS pathway in the aorta. Pretreatment with PKCβ inhibitor attenuated inhibitory effects of apoCIII. ApoCIII resides on VLDL fraction in the plasma, especially in the postprandial state. Injection of apoCIII-rich VLDL, but not apoCIII-deficient VLDL, also impaired these processes. Conclusion Our data suggest that apoCIII impairs insulin stimulation of NO production by vascular endothelium. This adverse effect of apoCIII is mediated by its activation of PKCβII which inhibits the IRS-1/PI3K/Akt/eNOS pathway. These results indicate that apoCIII not only modulates lipoprotein metabolism, but also may directly contribute to the development of diabetic complications through endothelial dysfunction. Finally, our results may point to a novel mechanism that links dyslipidemia, insulin resistance and endothelial dysfunction.

Abstract 153: Bile Acid Receptor TGR5 Agonism Represents Anti-inflammatory Effects via Stimulating Nitric Oxide Production in Vascular Endothelial Cells

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Taiki Kida ◽  
Yoshiki Tsubosaka ◽  
Masatoshi Hori ◽  
Hiroshi Ozaki ◽  
Takahisa Murata
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Bile Acids ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Lithocholic Acid ◽  
Signal Pathways ◽  
No Production ◽  
Vascular Endothelial ◽  
Anti Inflammatory

Objective TGR5, a membrane-bound, G-protein-coupled receptor for bile acids, is known to be involved in regulation of energy homeostasis and inflammation. However, little is known about the function of TGR5 in vascular endothelial cells. In the present study, we examined whether TGR5 agonism represents anti-inflammatory effects in vascular endothelial cells focusing on nitric oxide (NO) production. Methods and Results In human umbilical vein endothelial cells (HUVECs), treatment with taurolithocholic acid (TLCA), which has the highest affinity to TGR5 among various bile acids, significantly reduced tumor necrosis factor (TNF)-α-induced vascular cell adhesion molecule (VCAM)-1 protein expression and adhesion of human monocytes, U937. These effects were abrogated by a NO synthase (NOS) inhibitor, N G -Monomethyl-L-arginine (L-NMMA). In bovine aortic endothelial cells (BAECs), treatment with TLCA as well as lithocholic acid, which also has high affinity to TGR5, significantly increased the NO production. In contrast, deoxycholic acid and chenodeoxycholic acid, which possess low affinity to TGR5, did not affect the NO production. Gene depletion of TGR5 by siRNA transfection abolished TLCA-induced NO production in BAECs. TLCA-induced NO production was also observed in HUVECs measured as intracellular cGMP accumulation. We next investigated the signal pathways responsible for the TLCA-induced NO production in endothelial cells. Treatment with TLCA increased endothelial NOS (eNOS) ser1177 phosphorylation in HUVECs. This response was accompanied by increased Akt ser473 phosphorylation and intracellular Ca 2+ ([Ca 2+ ] i ). Treatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or blockade of calcium channel with La 3+ , significantly decreased TLCA-induced eNOS ser1177 phosphorylation and subsequent NO production. Conclusion These results indicate that TGR5 agonism can mediate anti-inflammatory responses by suppressing VCAM-1 expression and monocytes adhesion to endothelial cells. This function is dependent on NO production via Akt activation and [Ca 2+ ] i increase.

scholarly journals VE-PTP inhibition elicits eNOS phosphorylation to blunt endothelial dysfunction and hypertension in diabetes

2020 ◽  
Author(s):  
Mauro Siragusa ◽  
Alberto Fernando Oliveira Justo ◽  
Pedro Felipe Malacarne ◽  
Anna Strano ◽  
Akshay Buch ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Therapeutic Option ◽  
Diabetic Patients ◽  
No Production ◽  
Vascular Endothelial ◽  
Enos Activity

Abstract Aims Receptor-type vascular endothelial protein tyrosine phosphatase (VE-PTP) dephosphorylates Tie-2 as well as CD31, VE-cadherin, and vascular endothelial growth factor receptor 2 (VEGFR2). The latter form a signal transduction complex that mediates the endothelial cell response to shear stress, including the activation of the endothelial nitric oxide (NO) synthase (eNOS). As VE-PTP expression is increased in diabetes, we investigated the consequences of VE-PTP inhibition (using AKB-9778) on blood pressure in diabetic patients and the role of VE-PTP in the regulation of eNOS activity and vascular reactivity. Methods and results In diabetic patients AKB-9778 significantly lowered systolic and diastolic blood pressure. This could be linked to elevated NO production, as AKB increased NO generation by cultured endothelial cells and elicited the NOS inhibitor-sensitive relaxation of endothelium-intact rings of mouse aorta. At the molecular level, VE-PTP inhibition increased the phosphorylation of eNOS on Tyr81 and Ser1177 (human sequence). The PIEZO1 activator Yoda1, which was used to mimic the response to shear stress, also increased eNOS Tyr81 phosphorylation, an effect that was enhanced by VE-PTP inhibition. Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro. Finally, phosphorylation of eNOS on Tyr80 (murine sequence) was found to be reduced in diabetic mice and diabetes-induced endothelial dysfunction (isolated aortic rings) was blunted by VE-PTP inhibition. Conclusions VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE-cadherin/VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81. VE-PTP inhibition, therefore, represents an attractive novel therapeutic option for diabetes-induced endothelial dysfunction and hypertension.

scholarly journals Salidroside Stimulates Mitochondrial Biogenesis and Protects against H2O2-Induced Endothelial Dysfunction

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Shasha Xing ◽  
Xiaoyan Yang ◽  
Wenjing Li ◽  
Fang Bian ◽  
Dan Wu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Transcription Factor ◽  
Endothelial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Umbilical Vein ◽  
Adenosine Monophosphate ◽  
No Production ◽  
Peroxisome Proliferator ◽  
Atp Production

Salidroside (SAL) is an active component ofRhodiola roseawith documented antioxidative properties. The purpose of this study is to explore the mechanism of the protective effect of SAL on hydrogen peroxide- (H2O2-) induced endothelial dysfunction. Pretreatment of the human umbilical vein endothelial cells (HUVECs) with SAL significantly reduced the cytotoxicity brought by H2O2. Functional studies on the rat aortas found that SAL rescued the endothelium-dependent relaxation and reduced superoxide anion (O2∙-) production induced by H2O2. Meanwhile, SAL pretreatment inhibited H2O2-induced nitric oxide (NO) production. The underlying mechanisms involve the inhibition of H2O2-induced activation of endothelial nitric oxide synthase (eNOS), adenosine monophosphate-activated protein kinase (AMPK), and Akt, as well as the redox sensitive transcription factor, NF-kappa B (NF-κB). SAL also increased mitochondrial mass and upregulated the mitochondrial biogenesis factors, peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) in the endothelial cells. H2O2-induced mitochondrial dysfunction, as demonstrated by reduced mitochondrial membrane potential (Δψm) and ATP production, was rescued by SAL pretreatment. Taken together, these findings implicate that SAL could protect endothelium against H2O2-induced injury via promoting mitochondrial biogenesis and function, thus preventing the overactivation of oxidative stress-related downstream signaling pathways.

VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells

1998 ◽  
Vol 274 (3) ◽  
pp. H1054-H1058 ◽  
Author(s):  
John D. Hood ◽  
Cynthia J. Meininger ◽  
Marina Ziche ◽  
Harris J. Granger
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Umbilical Vein ◽  
Northern Blotting ◽  
No Production ◽  
Vascular Endothelial ◽  
Umbilical Vein Endothelial Cells ◽  
Oxide Synthase ◽  
Endothelial Growth Factor ◽  
Stimulation Of

Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted protein that potently stimulates vasodilation, microvascular hyperpermeability, and angiogenesis. Nitric oxide (NO) is also reported to modulate vascular tone, permeability, and capillary growth. Therefore, we hypothesized that VEGF might regulate endothelial production of NO. The production of nitrogen oxides by human umbilical vein endothelial cells (HUVECs) was measured after 1, 12, 24, and 48 h of incubation with VEGF. VEGF treatment resulted in both an acute (1 h) and chronic (>24 h) stimulation of NO production. Furthermore, Western and Northern blotting revealed a VEGF-elicited, dose-dependent increase in the cellular content of endothelial cell nitric oxide synthase (ecNOS) message and protein that may account for the chronic upregulation of NO production elicited by VEGF. Finally, endothelial cells pretreated with VEGF for 24 h and subsequently exposed to A-23187 for 1 h produced NO at approximately twice the rate of cells that were not pretreated with VEGF. We conclude that VEGF upregulates ecNOS enzyme and elicits a biphasic stimulation of endothelial NO production.

Abstract 18673: JNK Inhibition Restores Endothelial Function in Type 2 Diabetes Mellitus

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Rosa Breton-Romero ◽  
Bihua Feng ◽  
Monika Holbrook ◽  
Melissa G Farb ◽  
Jessica L Fetterman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Diabetic Patients ◽  
Jnk Activation

Introduction: Diabetes mellitus type 2 is an increasingly public health problem and it is a major cause in the development of cardiovascular diseases. Endothelial dysfunction is a key mechanism that contributes to the pathogenesis of cardiovascular diseases and is a well-known feature of clinical diabetes. Prior studies have demonstrated an impaired nitric oxide bioavailability and a reduced endothelium-dependent vasodilation under diabetic conditions and in animal models, JNK activity has been widely described to be involved in systemic insulin resistance. Hypothesis: Our study aimed to evaluate the involvement of JNK in endothelial dysfunction, studying its potential role in altered eNOS activation and NO synthesis in diabetic patients. Methods: We measured endothelial function and JNK activity in freshly isolated endothelial cells from diabetic patients (n=38) and nondiabetic controls (n=40). Results: ECs from diabetic patients displayed impaired eNOS activation and reduced NO release after insulin and A23187 stimulation, consistent with the presence of endothelial dysfunction. JNK activation was higher in diabetic (**P=0.003), and was associated with lower flow-mediated dilation (r=-0.53, *P=0.02). In endothelial cells from diabetic patients, treatment with JNK chemical inhibitor (SP600125) restored eNOS activation and insulin response (***P<0.001). Nitric oxide bioactivity after A23187 stimuli with diabetes was also recovered in endothelial cells from patients with diabetes. Conclusions: In summary, our data suggest that JNK activation contributes to vascular insulin resistance and endothelial dysfunction in patients with type 2 diabetes and may represent a target in novel therapeutic opportunities.

Abstract 141: Histone Deacetylase 1 Regulates Nitric Oxide Production and Nitric Oxide Synthase-3 Acetylation in Endothelial Cells

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Kelly A Hyndman ◽  
Dao H Ho ◽  
Jennifer S Pollock
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Histone Deacetylase ◽  
Life Stress ◽  
Trichostatin A ◽  
Early Life Stress ◽  
No Production ◽  
Histone Deacetylase 1 ◽  
Nitrite Production

Previous reports showed that NOS3 is regulated by acetylation through transcriptional mechanisms via histone acetylation or through direct lysine acetylation. Histone deacetylase (HDAC) enzymes and histone acetyltransferases (HATs) modulate acetylation processes. Recent work by our lab, demonstrated increased expression of aortic HDAC1 and HDAC6 while HATs were unchanged in a mouse model of early life stress with endothelial dysfunction. These data suggest a negative correlation between endothelial dysfunction and HDAC expression. The purpose of this study was to test the hypothesis that HDAC1 and 6 regulate endothelial NO production and/or NOS3 acetylation. Initial immunoprecipitation studies with anti-acetyl lysine and anti-NOS3 antibodies demonstrated that NOS3 is basally acetylated in primary bovine aortic endothelial cells (BAECs). Treatment with the HDAC inhibitor, trichostatin A (500 nM) for 1 hr, significantly increased NOS3 acetylation. BAECs were transfected with HDAC1, HDAC6, vector expression plasmids, or untransfected, with nitrite production determined by HPLC and NOS3 acetylation and expression probed by immunoprecipitation and Western blotting. Untransfected and vector transfected control BAECs had similar NO production (357 ± 10 and 344 ± 30 pmol/mg pr/h, respectively, N=6) as well as NOS3 acetylation (7.8 ± 1.6 and 6.8 ±0.3 AU, N=3). HDAC6 transfected BAECs had similar NO production to the control BAECs (272 ± 93 pmol/mg pr/h, N=3) with an increase in NOS3 acetylation (17.4 ± 1.7 AU, N=3). In contrast, HDAC1 overexpression significantly decreased NO production (89 ± 50 pmol/mg pr/h, P< 0.05, N=3) and reduced NOS3 acetylation (3.8 ± 0.5 A.U, N=3), P <0.05). Control transfections, HDAC6, and HDAC1 transfected BAECS all had similar NOS3 expression (10.14 ± 1.8; 9.8 ±1.6; 8.9 ± 1.5; 10.6 ± 1.0 AU, respectively, N=3). Thus, we conclude that HDAC1 regulates NO production via direct lysine deacetylation of NOS3.

scholarly journals High glucose-induced IKK-Hsp-90 interaction contributes to endothelial dysfunction

2009 ◽  
Vol 296 (1) ◽  
pp. C182-C192 ◽  
Author(s):  
Sumathy Mohan ◽  
Ryszard Konopinski ◽  
Bo Yan ◽  
Victoria E. Centonze ◽  
Mohan Natarajan
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
High Glucose ◽  
Vascular Endothelial Cells ◽  
Heat Shock Protein 90 ◽  
No Production ◽  
Enos Activity ◽  
Hsp 90 ◽  
Endothelial Nitric Oxide

A decline in the bioavailability of nitric oxide (NO) that causes endothelial dysfunction is a hallmark of diabetes. The availability of NO to the vasculature is regulated by endothelial nitric oxide synthase (eNOS) activity and the involvement of heat shock protein-90 (Hsp-90) in the regulation of eNOS activity has been demonstrated. Hsp-90 has been shown to interact with upstream kinases [inhibitor κB kinases (IKK)α, β, and γ] in nonvascular cells. In this study, we have investigated the interaction of Hsp-90-IKKβ in endothelial cells under conditions of high glucose (HG) as a possible mechanism that diminishes Hsp-90-eNOS interaction, which could contribute to reduced bioavailability of NO. We report for the first time that IKKβ interacts with Hsp-90, and this interaction is augmented by HG in vascular endothelial cells. HG also augments transcriptional (3.5 ± 0.65-fold) and translational (1.97 ± 0.17-fold) expression as well as the catalytic activity of IKKβ (2.45 ± 0.4-fold). Both IKKβ and eNOS could be coimmunoprecipitated with Hsp-90. Inhibition of Hsp-90 with geldanamycin (2 μM) or Radicicol (20 μM) mitigated (0.45 ± 0.04-fold and 0.93 ± 0.16-fold, respectively) HG induced-IKKβ activity (2.5 ± 0.42-fold). Blocking of IKKβ expression by IKK inhibitor II (15 μM wedelolactone) or small interferring RNA (siRNA) improved Hsp-90-eNOS interaction and NO production under conditions of HG. These results illuminate a possible mechanism for the declining eNOS activity reported under conditions of HG.

scholarly journals Activation of Endothelial Nitric Oxide Synthase by the Angiotensin II Type 1 Receptor

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5914-5920 ◽  
Author(s):  
Hiroyuki Suzuki ◽  
Kunie Eguchi ◽  
Haruhiko Ohtsu ◽  
Sadaharu Higuchi ◽  
Sudhir Dhobale ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Enos Gene ◽  
No Production ◽  
Hypertrophic Response ◽  
Cgmp Production ◽  
At1 Antagonist

Enhanced angiotensin II (AngII) action has been implicated in endothelial dysfunction that is characterized as decreased nitric oxide availability. Although endothelial cells have been reported to express AngII type 1 (AT1) receptors, the exact role of AT1 in regulating endothelial NO synthase (eNOS) activity remains unclear. We investigated the possible regulation of eNOS through AT1 in bovine aortic endothelial cells (BAECs) and its functional significance in rat aortic vascular smooth muscle cells (VSMCs). In BAECs infected with adenovirus encoding AT1 and in VSMCs infected with adenovirus encoding eNOS, AngII rapidly stimulated phosphorylation of eNOS at Ser1179. This was accompanied with increased cGMP production. These effects were blocked by an AT1 antagonist. The cGMP production was abolished by a NOS inhibitor as well. To explore the importance of eNOS phosphorylation, VSMCs were also infected with adenovirus encoding S1179A-eNOS. AngII did not stimulate cGMP production in VSMCs expressing S1179A. However, S1179A was able to enhance basal NO production as confirmed with cGMP production and enhanced vasodilator-stimulated phosphoprotein phosphorylation. Interestingly, S1179A prevented the hypertrophic response similar to wild type in VSMCs. From these data, we conclude that the AngII/AT1 system positively couples to eNOS via Ser1179 phosphorylation in ECs and VSMCs if eNOS and AT1 coexist. However, basal level NO production may be sufficient for prevention of AngII-induced hypertrophy by eNOS expression. These data demonstrate a novel molecular mechanism of eNOS regulation and function and thus provide useful information for eNOS gene therapy under endothelial dysfunction.

scholarly journals STUDY OF VASCULAR ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

2021 ◽  
pp. 81-89
Author(s):  
Maryna Stoikevych ◽  
Nataliia Nedzvetska ◽  
Nataliia Fedorova
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Endothelium ◽  
Bowel Disease ◽  
Reactive Hyperemia ◽  
Vascular Endothelial ◽  
Inflammatory Bowel

Abstract. Currently, inflammatory bowel disease (IBD) is the most complex and not fully resolved problem in modern gastroenterology. IBD, with its two main subtypes, Crohn's disease (CD) and ulcerative colitis (UC), is a complex multifactorial pathology caused by external and internal factors, including host genetics, the immune system, environmental factors, and the gut microbiome. The possible involvement of endothelial dysfunction is also discussed. There is evidence that in diseases characterized by chronic systemic inflammation, it affects the properties of the arteries and causes both endothelial dysfunction and changes in arterial stiffness. The aim is to study the functional state of the vascular endothelium in patients with inflammatory bowel diseases. Material and methods. A total of 69 patients with IBD aged 18 to 70 years (44.0 ± 1.4 years) were examined. All patients were divided into 2 groups depending on the nosology. 1st group consisted of 45 patients with UC, among them 23 women (51.1 %) and 22 men (48.9 %), 2nd group – 24 patients with HC, of which 14 women (58.3 %) and 10 men (41.7 %). To assess endothelial function, the method for determining endothelium-dependent vasodilation of the brachial artery (BA) in a test with reactive hyperemia was used to assess the change in BA diameter (dPA), a ATL PHILIPS HDI 5000 SONOS CT ultrasound machine with a 7.5 MHz linear transducer was used. The endothelial function index was calculated as the difference between dPA after decompression and the initial value, expressed as a percentage. The content of a soluble vascular cell adhesion molecule 1 (VCAM-1) was determined in blood serum by an enzyme immunoassay using a test system («Bender MedSystems GmbH», Austria) using an enzyme immunoassay analyzer «Stat Fax 303 Plus» («Awareness Technology Inc.», USA). The number of desquamated endothelial cells in the peripheral blood was determined by the method of J. Hladovec. Results. In the study of endothelium-dependent vasodilation (EDVD) PA in a test with reactive hyperemia, dysfunctions of the vascular endothelium were found in 75.4 % of the examined patients. Changes in vascular endothelial function were found in 82.3 % of patients with UC and 62.5 % with CC, mainly due to endothelial dysfunction (ED). Significant differences were found between the indicators of the average increase in dPA in the test with reactive hyperemia with decreased endothelial function (DEF) and normal endothelial function (NEF), as well as with DEF and ED in patients with severe UC. ED was observed 5.2 times more often than NEF (c2 = 56.8; p < 0.001) and 2.6 times more often than PFE (c2 = 31.5; p < 0.001). With moderate severity of the disease, DEF and ED occurred with the same frequency and 2.2 times higher than the number of patients with NEF (c2 = 11.3; p = 0.0008), changes in endothelium-dependent vasodilation were accompanied by a significant increase in the VCAM-1 level in serum of all IBD patients, but the highest expression of VCAM-1 was observed in UC. At the same time, the concentration of VCAM-1 was inversely correlated with endothelium-dependent vasodilation of BA (r = - 0.54, p < 0.01), which is confirmed by the quantitative characteristics of the level of VCAM-1 in various states of the endothelium. The study of the content of circulating desquamated endothelial cells in the peripheral blood made it possible to establish an increase in their number by 5 times with ED – up to (15.5 ± 4.8) × 104/L (p < 0.05), 2 times with DEF – up to (5.7 ± 0.3) × 104/L (p < 0.001) versus (3.1 ± 0.4) × 104/L in the control group. An inverse correlation was found between the number of desquamated endothelial cells and endothelium-dependent BA vasodilation (r = - 0.59, p < 0.01). Conclusions. The results of a comprehensive study of the functional state of the vascular endothelium indicate that the course of IBD is accompanied by a syndrome of endothelial dysfunction (with a predominance of DE), which is characterized by a decrease in endothelium-dependent vasodilation of BA, an increase in the level of VCAM-1 and the content of circulating desquamated endothelial cells in the blood. Keywords: inflammatory bowel disease, Crohn's disease, ulcerative colitis, endothelial dysfunction.

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