Induction Of Adhesion Molecules Research Articles

Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

It has been suggested that the teratogenic effects of the antiepileptic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferator-activated receptor delta (PPARdelta), and inhibition of histone deacetylases (HDACs). The aim of this study was to identify genes involved in the differentiation of F9 cells induced by VPA, teratogenic VPA derivatives, or the HDAC inhibitor trichostatin A (TSA) and to characterize the role of PPARdelta. Treatment of the cells with teratogenic VPA derivatives or TSA induced differentiation of F9 cells, mRNA, and protein expression of the neural cell adhesion molecule (NCAM) as well as activated the 5'-flanking region of the NCAM promoter, whereas nonteratogenic VPA derivatives had no effect at all. The polysialyltransferases [ST8SiaIV (PST1) and ST8SiaII] are responsible for the addition of polysialic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA derivatives and TSA. As shown by fluorescence-activated cell sorting analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA derivatives. It is interesting that overexpression of the PPARdelta but not PPARalpha or PPARgamma in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than in mock-transfected F9 cells. Furthermore, repression of PPARdelta activity in F9 cells inhibited these effects. We conclude that NCAM and PST1 are molecular markers in F9 cell differentiation caused by treatment with teratogenic VPA compounds or TSA and suggest that in addition to HDAC inhibition PPARdelta is involved in the signaling pathway.

Cancer and Inflammation

Cancer and Inflammation

Beyond Blood Pressure

Hypercholesterolemia and an activated renin-angiotensin-aldosterone system are well-established independent cardiovascular risk factors. Several lines of evidence support an important role of modified LDLs and angiotensin II in the development and progression of atherosclerosis. Angiotensin II is not only a potent vasoconstrictor, but it also promotes proinflammatory and prothrombotic properties of vascular cells. A growing body of in vitro studies shows the induction of cellular adhesion molecules and cytokines by angiotensin II in endothelial cells.1 In vivo, angiotensin II promotes leukocyte–endothelial cell interaction in the microcirculation. This proinflammatory mechanism involves the redox-sensitive mobilization of adhesion molecules such as P-selectin.2,3 These and several additional findings in cell systems and large vessels support a crucial role of the angiotensin II type-1 (AT1) receptor–mediated formation of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis.4,5 However, the impact of AT1 receptor antagonism on the accelerated inflammatory and thrombotic response and ROS formation by hypercholesterolemia has not been studied in the microvasculature in vivo so far. In this issue of Hypertension , Petnehazy et al provide experimental evidence for the …

Proatherosclerotic Mechanisms Involving Protein Kinase C in Diabetes and Insulin Resistance

In diabetes and insulin resistance, activation of protein kinase C (PKC) in vascular cells may be a key link between elevated plasma and tissue concentrations of glucose and nonesterified fatty acids and abnormal vascular cell signaling. Initial studies of PKC activation in diabetes focused on microvascular complications, but increasing evidence supports that PKC plays a role in several mechanisms promoting atherosclerosis. This review explains how PKC is thought to be activated in diabetes and insulin resistance through de novo synthesis of diacylglycerol. Furthermore, the review summarizes studies that implicate PKC in promoting proatherogenic mechanisms or inhibiting antiatherogenic mechanisms, including studies of endothelial dysfunction; gene induction and activation of vascular NAD(P)H oxidase; endothelial nitric oxide synthase expression and function; endothelin-1 expression; growth, migration, and apoptosis of vascular smooth muscle cells; induction of adhesion molecules; and oxidized low-density lipoprotein uptake by monocyte-derived macrophages.

Diverse effects of statins on endothelial cells?

T he vascular endothelium is a dynamic interface, normally providing a non-adhesive, non-thrombogenic surface for blood constituents. However, in response to proinflammatory stimuli from cytokines and bacterial products, or in response to vascular wall shear stress, induction of adhesion molecules and the expression of endothelial cell (EC) surface procoagulant proteins such as tissue factor (TF) may occur. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, are potent inhibitors of cholesterol synthesis in the mevalonate pathway. Clinical trials of statin therapy have demonstrated beneficial effects in primary and secondary prevention of coronary heart disease as well as ischemic stroke (1–6). Because mevalonate is a precursor of not only cholesterol, but also a variety of nonsteroidal isoprenoid compounds essential for normal cellular activity, the inhibition of HMGCoA reductase may have potential pleiotropic effects. Prenylation . . .

High-mobility group box 1: role in ARDS

Extracellular high-mobility group box 1 (HMGB-1), first isolated approximately 30 years ago from the thymus as a chromosomal protein and recognized as a transcriptional factor, has recently been proposed as one of the late mediators of sepsis and lipopolysaccharide (LPS) endotoxin acute lung injury (ALI) [1,2]. In recent studies, HMGB-1 has been implicated in the development of arthritis, activation of human monocytes, smooth muscle cell chemotaxis, and induction of adhesion molecules in endothelial cells. These observations suggest that HMGB-1 is a key mediator of cell injury, and that its inhibition may be key in improving clinical outcomes. We conducted a translational study to examine the participation of HMGB-1 in the pathogenesis of ALI caused by sepsis. To test the hypothesis that HMGB-1 plays a key role as a late mediator, we first measured its concentrations and those of its related compound, HMGB-2, in the blood and lungs of patients presenting with septic ALI/ARDS, and in a murine model of LPS-induced lung injury. We then studied the localization of the extracellular HMGB-1 protein and examined the anti-inflammatory effects of anti-HMGB-1 antibodies in our LPS-induced lung injury murine model. The direct effects of HMGB-1 and HMGB-2 on the lung were also examined. This study was performed to examine the putative role of HMGB protein in the pathogenesis of ALI. Observations were made (1) in 21 septic patients with ALI and 15 patients with normal lung function, and (2) in a mouse model, 24 hours after intratracheal instillation of lipopolysaccharide. The concentrations of HMGB-1 were increased in plasma and lung epithelial lining fluid of patients with ALI and mice instilled with LPS. LPS-induced ALI was mitigated by anti-HMGB-1 antibody. Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB-1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high. The nuclear expression of HMGB-1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, while its nuclear and cytoplasmic expression was observed in alveolar macrophages in LPS-instilled mice. Lung instillation of HMGB-2 did not cause as much inflammation as HMGB-1. Extracellular HMGB-1 may play a key role in the pathogenesis of clinical and experimental ALI. However, its expression in normal airways is noteworthy, and suggests that it also plays a physiologic role in the lung.

FK506 suppresses E-selectin, ICAM-1 and VCAM-1 expression on vascular endothelial cells by inhibiting tumor necrosis factor α secretion from peripheral blood mononuclear cells

FK506 suppresses activation of T cells; however, it down-regulates E-selectin, ICAM-1 and VCAM-1 expression in inflamed tissues. In this study, we investigated the effect of FK506 on expression of those adhesion molecules on human vascular endothelial cells (HMVEC). Culture supernatant from peripheral blood mononuclear cells (PBMC) stimulated with anti-CD3 plus anti-CD2 antibodies effectively induced the expression of E-selectin, ICAM-1 and VCAM-1 on HMVEC, and treatment with FK506 down-regulated their expression. Culture supernatant contained tumor necrosis factor (TNF) α and interleukin (IL)-1β, which effectively induced adhesion molecules, and FK506 suppressed both cytokine secretions. TNFα content in culture supernatant was parallel to the induction of adhesion molecules by the culture supernatant. IL-1β content was not enough to induce those adhesion molecules. Anti-TNFα antibody completely inhibited those expressions. FK506 did not inhibit either TNFα- or IL-1β-induced expression of adhesion molecules, or viability of HMVEC. These results indicate that FK506 suppresses migration of inflammatory cells through the inhibition of TNFα secretion from leukocytes.

Increased Plasma S100A12 (EN-RAGE) Levels in Patients with Type 2 Diabetes

S100A12, also called EN-RAGE (extracellular newly identified receptor for advanced glycation end products binding protein) or calcium-binding protein in amniotic fluid-1, is a ligand for RAGE. It has been shown that S100A12 induces adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in the vascular endothelial cell and mediates migration and activation of monocytes/macrophages through RAGE binding and that infusion of lipopolysaccharide into mice causes time-dependent increase of S100A12 in the plasma. Therefore, circulating S100A12 protein may be involved in chronic inflammation in the atherosclerotic lesion. In this study, we developed an ELISA system that uses specific monoclonal antibodies against recombinant human S100A12 to measure plasma S100A12 levels in patients with diabetes. On using our S100A12 ELISA system, the coefficients of variation of intra- and interassay were less than 4 and 9%, respectively. The analytical lower detection limit was 0.2 ng/ml. When plasma S100A12 levels were measured by this system, the concentrations were more than twice as high in the patients with diabetes, compared with those without. Using univariate analysis in all subjects, plasma S100A12 concentrations correlated with hemoglobin A1c, fasting glucose, high-sensitivity C-reactive protein and white blood cell count. Stepwise multiple regression analyses, however, revealed that only white blood cell count and hemoglobin A1c remained significant independent determinants of plasma S100A12 concentration. These results suggest that plasma S100A12 protein levels are regulated by factors related to subclinical inflammation and glucose control in patients with type 2 diabetes.

Histological effect and protein expression in subthreshold transpupillary thermotherapy in rabbit eyes.

To investigate the histological effect of subthreshold transpupillary thermotherapy (TTT) on the retina. We performed TTT in normal pigmented rabbit eyes using an 810-nm diode laser with spot size of 1.2 mm, power of 50 mW, and varying durations of 15, 30, or 60 seconds. Four weeks later, fluorescein angiography was performed, and the enucleated eyes were examined by means of electron microscopy and immunohistochemical staining. Funduscopy immediately and at 4 weeks showed no discernable changes at TTT sites, and fluorescein angiography at 4 weeks showed no abnormalities. However, electron microscopy showed photoreceptor and retinal pigment epithelium cell disruption, changes more prominent with longer durations of treatment. Immunohistochemical staining was positive for heat shock protein 60, heat shock protein 70, tumor necrosis factor alpha, and vascular cell adhesion molecule 1 in the photoreceptors and retinal pigment epithelium at TTT sites. Untreated control eyes showed no staining. Despite the absence of changes evident by funduscopy and fluorescein angiography, TTT resulted in dose-dependent histological changes in photoreceptors and retinal pigment epithelium. The induction of heat shock proteins, cytokines, and cell adhesion molecules may play a role in the tissue response to subthreshold TTT. Clinical Relevance Unrecognized damage to the retina and retinal pigment epithelium may contribute to visual loss in eyes that undergo subthreshold TTT.

Macrophage-mediated endothelial inflammatory responses to airborne particulates: impact of particulate physicochemical properties.

Epidemiological studies have implicated a role for airborne particulates of <2.5 microm diameter in the development/exacerbation of chronic cardiopulmonary disease; however, specific pathogenic mechanisms and the etiological significance of particle physicochemical properties remain unresolved. Using a microporous aluminosilicate zeolite Y as a manifold, we have synthesized 1 microm particulates of pure carbon (C), carbon-iron (C/Fe), and carbon-iron/fluoro-aluminum silicate (C-Fe/F-Al-Si). We have used these particulates, as well as coal fly ash (CFA) and diesel exhaust particulates (DEP), to test the hypotheses that human macrophages treated with particulates elaborate proinflammatory cytokines in quantities sufficient to induce endothelial adhesion molecule expression and that macrophage responses to particulate exposure vary as a function of particulate physicochemical properties. Human monocyte-derived macrophages (Mø) were exposed for 24 h to sublethal concentrations of particulates, at which time phagocytosis was evident from optical microscopy. Human arterial, microvascular, or venous endothelial cells (EC) were treated with clarified supernatants recovered from Mø cultures, stained with fluorescein-conjugated mononclonal antibodies specific for endothelial adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or E-selectin, and assayed by fluorescence flow cytometry. Data generated by these experiments demonstrate that while supernatants of Mø exposed to CFA and C particulates are relatively ineffective, supernatants from DEP, C/Fe, or C-Fe/F-Al-Si strongly induced adhesion molecule expression on EC, responses which were completely attenuated by antibody with blocking specificity for tumor necrosis factor alpha. Because the only difference between C and C/Fe particulates is the presence of surface iron on C/Fe, these findings suggest particulate-induced oxidative stress as a contributing factor in Mø activation and implicate redox active iron as a major determinant of particulate bioreactivity.

Inhibition of aldose reductase attenuates TNF-alpha-induced expression of adhesion molecules in endothelial cells.

Increased expression of adhesion molecules by the activated endothelium is a critical feature of vascular inflammation associated with several disease states such as atherosclerosis. However, mechanisms regulating the endothelial induction of adhesion molecules are not entirely clear. Herein we report that inhibition of the polyol pathway enzyme aldose reductase (AR) prevents the increase in ICAM-1 and VCAM-1 in human umbilical vein endothelial cells (HUVECs) and decreases monocyte adhesion to these cells. In TNF-alpha-stimulated HUVECs, treatment with AR inhibitors sorbinil and tolrestat diminished NF-kappaB activity, phosphorylation and degradation of Ikappa-Balpha, and the nuclear translocation of NF-kappaB. Inhibition of AR abrogated TNF-alpha-induced activation and membrane translocation of PKC, and antisense ablation of AR prevented both TNF-alpha-induced PKC and NF-kappaB activation. However, inhibition of AR did not prevent phorbol ester-induced activation of PKC or NF-kappaB, indicating that inhibition of AR does prevents events upstream of PKC activation. These results identify a novel regulator of endothelial activation and suggest that AR is an obligatory mediator of TNF-alpha signaling leading to an increase in the expression of adhesion molecules and increased binding of monocytes to the endothelium.

Synthesis of ether analogues derived from HUN-7293 and evaluation as inhibitors of VCAM-1 expression

The cyclic depsipeptide HUN-7293 ( 1) and its d-lactate analogue 2 are highly potent inhibitors of inducible cell adhesion molecule expression. We report the synthesis of ether analogues varying in stereochemistry and side chain at the former hydroxyl acid position by employing a ‘cut and paste chemistry’ methodology starting from 1. As an additional fruit of this synthetic effort, a cyclodepsipeptide featuring a tertiary amine instead of a tertiary amide between PrLEU and MALA was obtained. Results on the inhibitory profile of these compounds in assays of VCAM-1 and ICAM-1 protein expression are discussed.

Correction

Correction

IFN-gamma/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1.

We have previously shown that IFN-gamma/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-gamma/STAT1 also plays a crucial role in leukocyte infiltration into the liver in T cell hepatitis. After injection of ConA, leukocytes were significantly infiltrated into the liver, which was suppressed in IFN-gamma(-/-) and STAT1(-/-) mice. Disruption of the IFN regulatory factor-1 (IRF-1) gene, a downstream target of IFN-gamma/STAT1, abolished ConA-induced liver injury and suppressed leukocyte infiltration into the liver. Additionally, ConA injection induced expression of a wide variety of chemokines and adhesion molecules in the liver. Among them, expression of ICAM-1, VCAM-1, monokine induced by IFN-gamma (Mig), CC chemokine ligand-20, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IFN-inducible T cell-alpha chemoattractant (I-TAC), and IFN-inducible protein-10 (IP-10) was markedly attenuated in IFN-gamma(-/-), STAT1(-/-), and IRF-1(-/-) mice. In primary mouse hepatocytes, Kupffer cells, and endothelial cells, in vitro treatment with IFN-gamma activated STAT1, STAT3, and IRF-1, and induced expression of VCAM-1, ICAM-1, Mig, ENA-78, I-TAC, and IP-10 mRNA. Induction of these chemokines and adhesion molecules was markedly diminished in STAT1(-/-) and IRF-1(-/-) hepatic cells compared with wild-type hepatic cells. These findings suggest that in addition to induction of apoptosis, previously well documented, IFN-gamma also stimulated hepatocytes, sinusoidal endothelial cells, and Kupffer cells partly via an STAT1/IRF-1-dependent mechanism to produce multiple chemokines and adhesive molecules responsible for promoting infiltration of leukocytes and, ultimately, resulting in hepatitis.

Steady plasma concentration of unfractionated heparin reduces infarct volume and prevents inflammatory damage after transient focal cerebral ischemia in the rat.

Unfractionated heparin (UH) decreases the extent of infarction after transient focal brain ischemia in the rat and abridges neuroinflammatory damage in patients with acute stroke. This study was aimed at assessing whether controlled and steady heparinemia in plasma can reduce infarct volume and exert neuroprotective effects after ischemia. Infarct volume was measured at 24 and 7 days following a 1-hr intraluminal middle cerebral artery (MCA) occlusion in rats treated with UH or with vehicle. After testing several UH administration protocols, we choose to give a bolus of 200 U/kg, which was started 3 hr after the occlusion, followed by a 24-hr intraperitoneal perfusion of 70 U/kg/hr, which maintained a 24-hr steady plasma heparinemia (0.3-0.6 U/ml) and caused no CNS or systemic bleeding. In addition, plasma IL-10 concentration was measured by ELISA, endothelial VCAM-1 expression was evaluated by i.v. injection of a (125)I-labeled monoclonal antibody against VCAM-1, and brain hemeoxygenase-1 (HO-1) expression was determined by Western blot. UH-treated rats showed smaller infarctions than rats treated with vehicle, as well as higher IL-10 plasma levels and HO-1 brain expression and lower endothelial VCAM-1 induction. The study shows that a stable plasma concentration of UH given at nonhemorrhagic doses reduces infarct volume after ischemia-reperfusion in the rat. It also shows that UH prevented the induction of cell adhesion molecules in the cerebral vasculature and increased the expression of molecules with antiinflammatory and prosurvival properties. These findings support further testing of the clinical value of parenteral, adjusted, high-dose UH in patients with acute stroke.

Vascular cell adhesion molecule-1-targeted detection of endothelial activation in human microvasculature

The hallmark of endothelial activation, an early and critical step in many alloimmune and inflammatory responses, is the transcriptional induction and expression of endothelial adhesion molecules (eg, vascular cell adhesion molecule-1 [VCAM-1]). We assessed the feasibility of VCAM-1-targeted in vivo detection of endothelial activation using I-125-labeled-F(ab′) 2 fragments of E1/6, a monoclonal antibody against human but not murine VCAM-1. The K d and B max, determined by saturation binding in tumor necrosis factor (TNF)-activated human endothelial cells (ECs), were 3.2 ± 0.6 nmol/L and 5600 ± 300 binding sites per EC, respectively. Biodistribution and in vivo binding characteristics of I-125-E1/6 F(ab′) 2 were assessed in a novel chimeric human/mouse model, in which human skin (as a source of human microvasculature) is grafted onto SCID/beige mice. I-125-E1/6 F(ab′) 2 localized to TNF-activated human skin grafts as detected by autoradiography and gamma well-counting. Relative uptakes (uptake in human skin graft/uptake in the surrounding mouse skin) were, respectively, 2.6 ± 0.8 (n = 14) and 1.6 ± 0.3 (n = 12) for E1/6 and MOPC-21, an isotype-matched control antibody ( P < .01). The preferential uptake in human skin graft was not due to differences in tissue vascularity assessed by Tc-99m-labeled murine red blood cells. In conclusion, the chimeric human/mouse model is a novel experimental tool for in vivo evaluation of human endothelial cell-specific radiopharmaceuticals. Although I-125-E1/6 F(ab′) 2 localized to human skin grafts, the limited number of VCAM-1 molecules/endothelial cell adversely affects its suitability as a target for in vivo imaging of endothelial activation.

Mini-review: The nuclear protein HMGB1 as a proinflammatory mediator.

The intranuclear architectural protein that is termed high mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator when present extracellularly. HMGB1 has been demonstrated to be a long-searched-for nuclear danger signal passively released by necrotic, as opposed to apoptotic, cells that will induce inflammation. Furthermore, HMGB1 can also be actively secreted by stimulated macrophages or monocytes in a process requiring acetylation of the molecule, which enables translocation from the nucleus to secretory lysosomes. Subsequent transport out of the cells depends on a secretion signal mediated by either extracellular lysophophatidyl-choline or ATP. HMGB1 passively released from necrotic cells and HMGB1 actively secreted by inflammatory cells are thus molecularly different. Extracellular HMGB1 acts as a cytokine by signaling via the receptor for advanced glycated end-products and via members of the Toll-like receptor family. The initiated inflammatory responses include the production of multiple cytokines, chemoattraction of certain stem cells, induction of vascular adhesion molecules and impaired function of intestinal epithelial cells. Therapeutic administration of HMGB1 antagonists rescues mice from lethal sepsis, even when initial treatment is delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.

E-selectin is required for the antiangiogenic activity of endostatin.

Endostatin, a 20-kDa fragment of collagen XVIII, is a potent angiogenesis inhibitor. E-selectin, an inducible leukocyte adhesion molecule specifically expressed by endothelial cells, has also been implicated in angiogenesis. By using in vivo, ex vivo, and in vitro angiogenic assays, we investigated the functional relationship between endostatin and E-selectin. In corneal micropocket assays, recombinant endostatin administered i.p. by osmotic pump inhibited basic fibroblast growth factor-induced angiogenesis in WT, but not E-selectin-deficient, mice. Similarly, endostatin inhibited vascular endothelial growth factor-stimulated endothelial sprout formation from aortic rings dissected from WT but not from E-selectin-deficient mice. To further explore this apparent requirement for E-selectin in endostatin action, we manipulated E-selectin expression in cultured human endothelial cells. When E-selectin was induced by IL-1beta, or lipopolysaccharide, human umbilical vein endothelial cells and human dermal microvascular endothelial cells each became markedly more sensitive to inhibition by endostatin in a vascular endothelial growth factor-induced cell migration assay. To dissociate E-selectin expression from other consequences of endothelial activation, human umbilical vein endothelial cells were transduced with an adenoviral human E-selectin expression construct; these cells also showed increased sensitivity to endostatin, and this effect required the E-selectin cytoplasmic domain. Taken together, these results indicate that E-selectin is required for the antiangiogenic activity of endostatin in vivo and ex vivo and confers endostatin sensitivity to nonresponsive human endothelial cells in vitro. E-selectin may be a useful predictor and modulator of endostatin efficacy in antiangiogenic therapy.

Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates

Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, a remarkable induction was detected in the genes for syndecan-4 (SDC4) and alpha5-integrin (ITGA5), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis.

Oxidative stress and inflammation in plaque instability—role of vascular C-reactive protein

Disruption of vulnerable plaques is the main cause of acute coronary syndrome (ACS). It was reported that reactive oxygen species (ROS) activate matrix metalloproteinases. Therefore, the oxidative stress likely plays an important role in atherogenesis as well as plaque instability. Recent investigations demonstrated the presence of CRP, a potent risk factor of cardiovascular disease, in atherosclerotic vessels, and that CRP has direct pro-inflammatory effects on vascular cells such as induction of adhesion molecules and chemokines. In this review, we discuss the interaction of oxidative stress and inflammatory response in the plaque instability focusing on CRP.