Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells.

Khan, Bobby V.; Parthasarathy, S.; Alexander, R. Wayne; Medford, Russell M.

doi:10.1172/jci117776

Cited by 428 publications

(222 citation statements)

References 43 publications

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“…In contrast to previous studies (15,24), LPC does not contribute to the effects of oxLDL. This is consistent with results showing that effects of oxLDL are not necessarily mediated by LPC (25). Optimal treatment with LPC requires binding to BSA (24), causing differences in effectiveness.…”

Section: Monocyte Adhesion To Oxidized Low Density Lipoprotein-stimulsupporting

confidence: 91%

Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions

Weber¹,

Erl²,

Weber³

et al. 1999

CCLM

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The integrin heterodimer CD11b/CD18 (␣M␤2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2␣ (8-epi-PGF2␣) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear-resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet ␣IIb␤3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac-1-mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro, indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs.

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Section: Monocyte Adhesion To Oxidized Low Density Lipoprotein-stimulsupporting

confidence: 91%

Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions

Weber¹,

Erl²,

Weber³

et al. 1999

CCLM

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“…Glycaemic control in NIDDM patients could therefore be related to E-selectin plasma concentration, through its effect on the parameters correlated to oxidative stress. In this context, exciting recent findings indicated that oxidized LDL and plasma hydroperoxides can affect the expression of adhesion molecules on endothelial cells in vitro [26,27]. Additional evidence that the adhesion molecule expression on endothelial cells is an oxidative stress-responsive event comes from the inhibitory effects of various structural antioxidants in response to many different stimuli [27].…”

Section: Discussionmentioning

confidence: 99%

“…An enhanced oxidative stress, i. e. increased levels of plasma hydroperoxides, has actually been observed in NIDDM [20][21][22][23][24]. The augmented generation of free radicals could also result in oxidative damage of LDL, the known potentially atherogenic properties of oxidized LDL including monocyte recruitment [25] and modulation of expression of adhesion molecules [26,27]. Enhanced susceptibility of LDL to oxidation has recently been reported in diabetic patients [24,28,29].…”

mentioning

confidence: 99%

E-Selectin plasma concentration is influenced by glycaemic control in NIDDM patients: possible role of oxidative stress

Cominacini¹,

Pasini²,

Garbin³

et al. 1997

Diabetologia

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Atherosclerosis is the major cause of death in patients with diabetes mellitus, accounting for more than 70 % of mortality in all forms of the disease [1,2]. There is plenty of evidence that monocytes are involved in the pathogenesis of atherosclerosis [3,4], the earliest morphological evidence of the disease being the binding of monocytes to the endothelium [5][6][7]. This adhesion of monocytes, a prerequisite for their recruitment and accumulation in the lesion, is probably due to the appearance of adhesion Diabetologia (1997) Summary Although elevated levels of soluble E-selectin and intercellular cell adhesion molecules-1 (ICAM-1) have been reported in non-insulin-dependent diabetes mellitus (NIDDM), it is not clear by what mechanism this elevation occurs and whether or not it is related to glycaemic control. In this study we analyse: 1) the relation of glycaemic control with the concentrations of E-selectin, vascular cell adhesion molecules-1 (VCAM-1) and ICAM-1 in NIDDM patients; 2) whether metabolic control can affect the oxidative stress (as measured by plasma hydroperoxide concentration and susceptibility of LDL to in vitro oxidation) and hence the adhesion molecule plasma concentrations. Thirty-four (19 males and 15 females) poorly controlled NIDDM patients were studied. All parameters were evaluated at the beginning of the study and after 90 days of dietary and pharmacological treatment. The treatment decreased HbA 1C (p < 0.001), E-selectin (p < 0.001), plasma hydroperoxides (p < 0.003) and the susceptibility of LDL to in vitro oxidation (lag phase) (p < 0.0001). Before treatment HbA 1C , lag phase and lipid hydroperoxides correlated with E-selectin plasma concentration (r = 0.51, -0.57 and 0.54, respectively, p < 0.01). There was also a correlation between HbA 1C and lag phase (p < 0.01) and between HbA 1C and lipid hydroperoxides (p < 0.01). In addition, the variations of HbA 1C , lag phase and lipid hydroperoxide values correlated with those for E-selectin concentration after 90 days' treatment (r = 0.54, -0.64 and 0.61, respectively, p < 0.01). In multiple linear correlation analysis, however, the partial correlation coefficients of HbA 1C (basal and variations) with Eselectin concentration (basal and variations) fell to non-significant values (r = 0.12 and 0.25, respectively) when LDL lag phase and plasma hydroperoxides were kept constant. The results indicate that the improvement of metabolic control in NIDDM patients is associated with a decrease of E-selectin plasma levels; they also suggest that glycaemic control per se is not directly implicated in determining E-selectin plasma concentration; glycaemic control could affect E-selectin concentration through its effect on oxidative stress. [Diabetologia (1997) 40: 584-589]

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“…The leading hypothesis for atherogenesis is that it is due to an excessive fibroproliferative response to arterial injury [2]. One scenario for this injury is that lipoprotein is trapped in the arterial intima where it is oxidized, leading to the induction of endothelial adhesion molecules such as VCAM-1 [3]. Via these adhesion molecules, monocytes and T cells enter the arterial wall where the monocytes differentiate into macrophages.…”

Section: Introductionmentioning

confidence: 99%

The emergence of mouse models of atherosclerosis and their relevance to clinical research

Smith

Breslow

1997

Journal of Internal Medicine

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Due to the ability to introduce or mutate genes, the mouse has become the most common experimental animal model for atherosclerosis research. Wildtype mice on a chow diet do not get atherosclerosis. Three ways to induce atherosclerosis in mice are discussed: diet-induced, apoE deficiency-induced, and LDL receptor-deficiency induced. The atherosclerotic lesions in apoE-deficient mice have been well characterized, and they resemble human lesions in their sites of predilection and progression to the fibroproliferative stage. These mouse models of atherosclerosis are being used to identify genes which modify atherosclerosis susceptibility and in the development of antiatherogenic therapies.

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Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells.

Abstract: IntroductionEarly features in the pathogenesis of atherosclerosis include accumulation of oxidized LDL (oxLDL) and endothelial expression of the vascular adhesion molecule VCAM-1.

Cited by 428 publications

References 43 publications

Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions

Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions

E-Selectin plasma concentration is influenced by glycaemic control in NIDDM patients: possible role of oxidative stress

The emergence of mouse models of atherosclerosis and their relevance to clinical research

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