Atherosclerosis adhesion molecules

Oxidatively modified LDL up-regulates the surfece expression of VCAM-1 and intracellular adhesion molecule-1 (ICAM-1) in cultured endothelial cells, promoting the interactions between both cell types (Kume et al., 1992). This may play a pivotal role in the development of atherosclerosis by promoting the penetration of circulating monocytes into the suben-dothelial space whilst inhibiting the mobility of resident macrophages. It has been previously demonstrated that ICAM-1, E-selectin, and VCAM-1 are up-regulated in the microvasculature of rheumatoid but not control synovium (Corkill et al., 1991 Koch et al., 1991). The association between ox-LDL and increased expression of adhesion molecules in the inflamed synovium has yet to be studied. 

Fig. 9.1. A dysfunctional or injured endothelium is at the basis for initiation of and progression to atherosclerosis. Several mechanisms, such as adhesion molecules or liberation of von Willebrand factor (vWf, upper panel), determine a series of phenomena, including platelet activation and aggregation. This participation of platelets involves the implication of molecules like glycoprotein Ilb/IIIa, fibrinogen, and von Willebrand factor. The endothelium also acts as a source of signals that regulate local functions, including VSMCs (lower panel). A list of the most relevant messengers produced by a functional and a dysfunctonal endothelium is presented in the lower panel...

Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr, Boerwinkle E (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96 4219-4225... 

NO also reduces endothelial adhesion of monocytes and leukocytes, key features of the early development of atheromatous plaques. This effect is due to the inhibitory effect of NO on the expression of adhesion molecules on the endothelial surface. In addition, NO may act as an antioxidant, blocking the oxidation of low-density lipoproteins and thus preventing or reducing the formation of foam cells in the vascular wall. Plaque formation is also affected by NO-dependent reduction in endothelial cell permeability to lipoproteins. The importance of eNOS in cardiovascular disease is supported by experiments showing increased atherosclerosis in animals deficient in eNOS by pharmacologic inhibition. Atherosclerosis risk factors, such as smoking, hyperlipidemia, diabetes, and hypertension, are associated with decreased endothelial NO production, and thus enhance atherogenesis. 

Halichlorine (1) (Fig. 11.1) is an alkaloid which was isolated from the marine sponge H. okadai Kadota (Kuramoto et ah, 1996). This compound was revealed to be a novel alkaloid containing an azaspiro[4.5]decane skeleton clarified by detailed spectroscopic analyses. The absolute stereostructure was confirmed by many synthetic studies (Arimoto et ah, 1998 Clive et ah, 2005 Liu et ah, 2009 Trauner et ah, 1999). Halichlorine was shown to inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1) in cultured human umbilical vein endothelial cells. Drugs that block the inflammatory stimuli-induced expression of VCAM-1 may be useful for treating atherosclerosis, coronary artery diseases, angina, and noncardiovascular inflammatory diseases (Kock et ah, 1995). We introduce here the recent aspects of the biological and physiological activities of halichlorine. 

Various adhesion molecules are reported to be expressed on vascular endothelial cells at sites of inflammation (Libby, 2002). In fact, VCAM-1, expressed on the surface of vascular endothelial cells in response to inflammatory stimuli, is suggested to play an important role in leukocyte recruitment (Gerrity et al, 1979). The adhesion of monocytes to vascular endothelial cells is the first critical step in the induction of atherosclerosis (Glass and Witztum, 2001). Supportively, the expression of VCAM-1 is reported to increase in atherosclerosis lesions (Cybulsky and Gimbrone,... 

As described above, halichlorine was shown to inhibit LPS-induced events in BAECs, including adhesion-molecule expression, adherence of monocytes, and NF- activation. Thus, halichlorine is thought to be an attractive candidate for the adjunctive therapy of diseases such as atherosclerosis. 

Recent evidence suggests that atherosclerosis is a chronic inflammatory process. The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Alterations of chemotactic and adhesive properties of the endothelium play an important role in this process [82]. Quercetin has been reported to inhibit the expression in glomerular cells of monocyte chemoattractant protein-1 (MCP-1) [83] a potent chemoattractant for circulating monocytes. Red wine reduced MCP-1 mRNA and protein expression in abdominal aorta of cholesterol fed rabbits after balloon injury and this effect was associated with a reduced neointimal hyperplasia [84]. The antioxidant-mediated inhibition of nuclear factor k B (NFkB) and the subsequent non selective reduction of cytokine transcription have been suggested to be responsible for these effects [83]. Additionally, quercetin downregulated both phorbol 12-myristate 13-acetate (PMA)- and tumour necrosis factor-a (TNFa)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human endothelial cells [86]. 

The quinolizidine alkaloid halichlorine (203), isolated from the marine sponge Halichondria okadai, inhibits the induction of vascular cell adhesion molecule-1 (VCAM-1) at IC50 7 pg/ml, which may be useful for treating atherosclerosis, coronary artery diseases, angina and noncardiovascular inflammatory diseases [161]. 

Tribolo S, Lodi F, Connor C, Suri S, Wilson VG, Taylor MA, Needs PW, Kroon PA, Hughes DA. 2008. Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 197 50-56. 

Nomura S, Tandon NN, Nakamura T, Cone J, Fukuhara S, Kambayashi J. High-shear-stress-induced activation of platelets and microparticles enhances expression of cell adhesion molecules in THP-1 and endothelial cells. Atherosclerosis 2001 158 277-287. 

Increases in plasma S-AA levels have previously been reported in patients with coronary disease (57). S-AA and plasma intracellular adhesion molecule-1 were elevated in patients with CAD and hyperhomocysteinemia, but only S-AA decreased after vitamin supplementation (35). Homocysteine activates nuclear factor- in endothelial cells, possibly via oxidative stress (58), and increases monocyte chemoattractant protein-1 expression in vascular smooth muscle cells (59). Additionally, it stimulates interleukin-8 expression in human endothelial cultures (60). These inflammatory factors are known to participate in the development of atherosclerosis. Taken together, these reports suggest an association of elevated tHcy and low-grade inflammation in CAD. 

As with atherosclerosis itself, recruitment of inflammatory cells is now recognized as an essential step in the pathogenesis of neointima formation in humans (I 1,12). In various animal models, reduction of leukocyte recruitment by selective blockade of adhesion molecules significantly reduced neointima formation and restenosis (13-16). Recent studies also concluded a role of pre-existing inflammation within the... 

O Brien K, McDonald TO, Chart A, etal. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 1996 93 672-682. 

Tummala, P. E., Chen, X. L., Sundell, C. L., et al. 1999. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature A potential link between the renin-angiotensin system and atherosclerosis. Circulation 100 1223-1229. 

The earliest feature in atherosclerosis is the adherence of blood monocytes to arterial endothelial cells [23]. Interleukin 1 is a candidate for the adhesion molecule on endothelial cells [24], Then, adherent monocytes migrate into the intima under the influence of chemotactic factors. 

Oxidised LDL in the artery wall initiates a series of reactions designed to repair the damage it causes. Initial damage triggers an inflammatory response. Monocytes enter the artery waU from the bloodstream, with platelets adhering to the area of insult. This may be promoted by induction of factors such as vascular ceU adhesion molecule 1 (VCAM-1), a cell-surface sialoglycoprotein that is expressed by cytokine-activated endothelium. This membrane protein mediates leukocyte-endothelial cell adhesion and signal transduction, and may play a role in the development of atherosclerosis and rheumatoid arthritis. 

An interesting link between inflammation, atherosclerosis and NOS has been recently described [60]. In this study, the stimulation of iNOS through endothelin resulted in an increased production of NO, along with a concurrent suppression of the expression of vascular cell adhesion molecule-1 (VCAM-1). It is well known that a hallmark of inflammation is the adhesion of leukocytes to post-capillary venular endothelium and the consequent infiltration of leukocytes into the tissue interstitium. NO, by modulating cytokine-induced ECAM expression through the regulatory factor kB, may here act as antiinflammatory, keeping under control the very basic mechanisms of the atherosclerotic lesion. 

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