Osteopontin in Vascular Disease

Abstract

Inflammatory cytokines are necessary for an acute response to injury and the progressive healing process. However, when this acute response does not resolve and becomes chronic, the same proteins that once promoted healing then contribute to chronic inflammatory pathologies, such as atherosclerosis. OPN (Osteopontin) is a secreted matricellular cytokine that signals through integrin and CD44 receptors, is highly upregulated in acute and chronic inflammatory settings, and has been implicated in physiological and pathophysiologic processes. Evidence from the literature suggests that OPN may fit within the Goldilocks paradigm with respect to cardiovascular disease, where acute increases are protective, attenuate vascular calcification, and promote postischemic neovascularization. In contrast, chronic increases in OPN are clinically associated with an increased risk for a major adverse cardiovascular event, and OPN expression is a strong predictor of cardiovascular disease independent of traditional risk factors. With the recent finding that humans express multiple OPN isoforms as the result of alternative splicing and that these isoforms have distinct biologic functions, future studies are required to determine what OPN isoform(s) are expressed in the setting of vascular disease and what role each of these isoforms plays in vascular disease progression. This review aims to discuss our current understanding of the role(s) of OPN in vascular disease pathologies using evidence from in vitro, animal, and clinical studies. Where possible, we discuss what is known about OPN isoform expression and our understanding of OPN isoform contributions to cardiovascular disease pathologies.

Keywords: atherosclerosis; cytokines; inflammation; osteopontin; risk factors; vascular diseases.

Figure 1.. OPN isoform primary domain structure.

Each block corresponds to an exon (numbered). OPNa is full length (top; 314 aa), OPNb lacks exon 5 (middle; 300 aa), and OPNc lacks exon 4 (bottom; 287 aa). Expanded amino acid sequences of exons 4 and 5, absent in OPNc and OPNb, respectively, are included and glutamine residues (Q) that are potential sites for transglutamination are indicated in blue. Also indicated are OPN structural features and cleavage sites present within each exon. Corresponding amino acid numbers listed are for the OPNa isoform (with Met as aa 1).