Effect of MMP-2 on CCL2/MCP-1 in the migration and recruitment of macrophages in atherosclerosis

• Grant number: 12/15807-4
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2012
• End date: September 30, 2014
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Raquel Fernanda Gerlach
• Grantee: Raquel Fernanda Gerlach
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Atherosclerosis is a major cause of morbidity and mortality worldwide. The chemokine CCL2/MCP-1 (monocyte chemotactic protein-1) is considered responsible for the recruitment of monocytes and macrophage differentiation. Matrix metalloproteinase-2 (MMP-2) is associated with the development of atherosclerotic thrombi and their destabilization. However, there is an important controversy in the literature regarding the relationship between MMP-2 and CCL2. Some studies show that CCL2 enhances the activity of MMP-2 and potentiates the proinflammatory state. Other studies, mostly carried out in vitro, showed that MMP-2 cleaves CCL2, showing an anti-inflammatory action. This study has 3 aims. The first of which is to evaluate the effect of MMP-2 on CCL2/MCP-1 in atherosclerotic (ApoE-/-) chronically exposed to high concentrations of exogenous MMP-2 by evaluating the number of macrophages in atherosclerotic lesions by immunohistochemistry, as well as to assess their relationship with the general characteristics and the size of lesions using different histological techniques. The second objective is to evaluate the CCL2 action (and the possible effect of MMP-2 on CCL2 cleavage) by testing macrophage migration in vitro and in vivo. If an important effect of MMP-2 on CCL-2 action is observed in this study, the last objective of this project will be the biochemical characterization of the cleavage promoted by MMP-2 on the recombinant CCL-2 by means of MALD-TOF-TOF and Western blot analyses. The questions proposed here are crucial for the understanding of the relationship between MMP-2 and atherosclerosis, particularly on the CCL2/CCR2 axis, and the role of MMP-2 on the migration of monocytes and macrophage differentiation. (AU)