An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium.

Abstract

Accumulation of monocyte-derived foam cells in focal areas of the arterial intima is a key step in early atherogenesis. We investigated the expression of vascular cell adhesion molecule-1 (VCAM-1), a mononuclear leukocyte adhesion molecule, in the arterial endothelium during the early phases of diet-induced atherogenesis in rabbits in vivo and the regulation of VCAM-1 expression by cytokines in rabbit aortic organoid cultures in vitro. Rabbits were fed either an atherogenic diet (containing 0.3% cholesterol, 9% coconut oil, and 1% corn oil) or an isocaloric control diet (10% corn oil) for 4 days or 1, 3, 6, or 13 weeks. The endothelium in the ascending aorta focally expressed VCAM-1 after only 1 week on the atherogenic diet but before the first appearance of intimal macrophages, as judged by immunohistochemical staining of serial sections. The rabbits that consumed the atherogenic diet for 3 weeks or longer developed lesions in the intima composed of macrophages bearing class II major histocompatibility antigen (MHC-II). Endothelial cells continued to focally express VCAM-1 at sites of MHC-H-positive intimal macrophages for up to 13 weeks. The ascending aortas of control rabbits lacked VCAM-1 or MHC-II-positive endothelium or macrophages at all times studied. These observations demonstrate the focal activation of arterial endothelium as early as 7 days after initiation of an atherogenic diet (at serum cholesterol levels of 308 ±57 mg/dl). In organoid cultures of rabbit thoracic aortas, Gram-negative bacterial lipopolysaccharide or the cytokines interleukin (IL)-lcx, tumor necrosis factor-**, and IL-4, as well as interferon gamma, induced VCAM-1 expression in the endothelium. Our results suggest that the activation of cytokine-inducible endothelial functions, such as expression of VCAM-1, may participate in the initiation of diet-induced atherosclerosis in rabbits. ( 4 -6 Alterations in adhesive properties of the vascular endothelial surface due to the induction of endothelial-leukocyte adhesion molecules (ELAMs) might contribute to monocyte recruitment in the arteries of hypercholesterolemic animals. Among the several ELAMs identified and structurally characterized to date, vascular cell adhesion molecule-1 (VCAM-1) holds particular interest in regard to the initiation of macrophage-rich fatty streak lesions because of its functional specificity and pattern of expression.VCAM-1, a member of the immunoglobulin (Ig) gene superfamily, is a mononuclear leukocyte-selective adhesion molecule expressed in cultured human vascular endothelial cells (ECs) after activation by lipopolysaccharide (LPS) and certain cytokines, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and This inducible EC surface molecule mediates intercellular adhesion via interaction with its counterreceptor,

Dual Roles for Lipolysis and Oxidation in Peroxisome Proliferation-Activator Receptor Responses to Electronegative Low Density Lipoprotein

“…This occurs in part through the induction of early atherogenic inflammatory responses, including the expression of adhesion molecules like VCAM1 by endothelial cells (ECs) (3,4). Consistent with this, increased dietary cholesterol rapidly induces atherosclerosis in animal models, with changes in VCAM1 expression seen within 2 weeks (3).…”

Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells.

“…This is likely due in part to both paracrine and autocrine mechanisms by which the cytokines IL-1l3 and TNFa, derived from both inflammatory and endothelial cells, induce the cellular synthesis ofreactive oxygen species ( 19,20). It is in this oxidative milieu that endothelial VCAM-I expression and consequent monocyte accumulation is observed in the early atherogenic lesion (3,21 ). These observations suggest that the activation of VCAM-1 gene expression might be distinguished by its sensitivity to modulation by oxidation-mediated signals.…”

Using Antibody Arrays to Detect Microparticles from Acute Coronary Syndrome Patients Based on Cluster of Differentiation (CD) Antigen Expression

“…Receptors such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 are up-regulated on the endothelium in response to noxious stimuli (8). These molecules couple with the integrins expressed on rolling leukocytes and adhere these leukocytes to the endothelium (9).…”