Deamidation of extracellular matrix proteins and its effect on integrin signalling and cytokine secretion

Abstract

Endothelial dysfunction and vascular inflammation trigger development of atherosclerosis by leukocyte recruitment and lipid accumulation within the arteries. Early phase of atherogenesis constitutes of macrophage recruitment to the site of vascular injury. However, the underlying molecular events are not fully understood. Deamidation of asparagine (Asn) residue in proteins with Asn-Gly-Arg (NGR) motif generates a new gain-of-function motif isoAsp-Gly-Arg (isoDGR), which mimics Arg-Gly-Asp (RGD) motif and interacts with surface integrins of leukocytes for cell migration and adhesion. This study has reinforced that deamidation of extracellular matrix (ECM) proteins (fibronectin) enhances monocytic U937 cell adhesion and may implicate in the pathology of age-related cardiovascular disease (CVD). My research project further demonstrates that enhanced monocytic cell adhesion, due to isoDGR binding, induced an outside-in signalling in U937 cells and resulted in increased expression level of proinflammatory cytokines that are strongly associated with atherosclerosis. Interestingly, integrin signalling pathway mediated by fibronectin-integrin binding, together with Protein Kinase C (PKC) activation by Phorbol 12-myristate 13-acetate (PMA), was identified to be MAPK-ERK pathway, but not PI3K-Akt pathway. Collectively, these data suggest the important role of isoDGR motif in enhancing monocytic adhesion and may promote the progression of atherosclerosis by intensifying leukocyte recruitment to the atherosclerotic plaques via increased cytokine secretion.