Cyclic arginine-glycine-aspartic acid peptide inhibits macrophage infiltration of the kidney and carotid artery lesions in apo-E-deficient mice

Abstract

Elitok, Saban, Sergey V. Brodsky, Daniel Patschan, Tatyana Orlova, Kenneth M. Lerea, Praveen Chander, and Michael S. Goligorsky. Cyclic arginine-glycine-aspartic acid peptide inhibits macrophage infiltration of the kidney and carotid artery lesions in apo-Edeficient mice. Am J Physiol Renal Physiol 290: F159 -F166, 2006. First published August 16, 2005 doi:10.1152/ajprenal.00227.2005Interactions of leukocytes with the vascular endothelium culminating in their diapedesis represent not only a crucial event in immune surveillance and defense but are also critically involved in the pathogenesis of many inflammatory diseases, including atherosclerosis. Our previous in vitro studies using atomic force microscopy measurement of monocyte-endothelial cell interaction have demonstrated that a cyclic arginine-glycine-aspartic acid peptide (cRGD) inhibited their adhesion through very late antigen (␣ 4␤1-integrin; VLA4)-vascular cell adhesion molecule-1 by 60% with the IC50 ϭ 100 nM. To elucidate the potential efficacy of this peptide in vivo in preventing atherogenesis, experiments were performed in apolipoprotein E (ApoE)-deficient (Ϫ/Ϫ) mice fed a Western diet and receiving chronic treatment with cRGD peptide for 2-4 wk. In addition, some animals were subjected to a temporary carotid artery ligation while receiving the above treatment. Formation of fatty streaks and infiltration of the vascular wall with macrophages were not affected by cRGD treatment. Infiltration of the carotid artery postligation was significantly reduced in the cRGD-treated animals, as was the lipid accumulation. Furthermore, cRGD-treated ApoE Ϫ/Ϫ mice exhibited significantly lesser macrophage infiltration and lipid accumulation in the kidneys, the site of the highest expression of VLA4. These data demonstrated that cRGD peptide is a potent inhibitor of monocyte/ macrophage infiltration of the injured macrovasculature and of the renal microvasculature, where it results in the attenuation of lipid accumulation. Formation of fatty streaks in the aortic root was not inhibitable by this treatment.atherosclerosis; apolipoprotein E; VLA-4; kidney; lipid accumulation INTERACTIONS OF LEUKOCYTES with the vascular endothelium culminating in their diapedesis represent not only a crucial event in immune surveillance and defense but are also critically involved in the pathogenesis of many inflammatory diseases, including atherosclerosis. The process of leukocyte egress has been tentatively subdivided into stages of rolling, cell activation, firm adhesion, and transendothelial migration (TEM), with each stage engaging a distinct set of adhesion molecules and their activation (5, 13, 26). These adhesion molecules include L-selectin; carbohydrate ligands of selectins; ␤ 1 -, ␤ 2 -, and ␤ 7 -integrins; and platelet endothelial cell adhesion molecule (PECAM)-1 on leukocytes, and P-and E-selectins, intercellular adhesion molecule (ICAM)-1 and ICAM-2, vascular cell adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule-1 (MadCAM-1), PECAM-1 and ␤ 1 -integr...

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