Osteopontin Is Elevated in AAA and May Drive Disease Progression

Abstract

Previous in vitro and animal studies have suggested the importance of osteopontin (OPN), an inflammatory extracellular matrix (ECM) protein, in the formation and growth of abdominal aortic aneurysms (AAAs). The relationship between OPN and the inflammatory cell phenotypes present in the human AAA condition was investigated. Serum OPN concentrations were measured in risk-factor matched non-AAA and AAA patients by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to determine the source of OPN secretion using tissue collected from multiorgan donors and AAA patients undergoing open repair. Vascular smooth muscle cells (VSMCs) were exposed to inflammatory mediators, and the OPN response was evaluated by quantitative RT-PCR and ELISA. The inflammatory nature of OPN and the aortic wall was then determined using a T regulatory cells type 1 (TR1) suppressor cell induction assay. CD45RO– cells were induced to the TR1 suppressor cell phenotype through the action of high-molecular-weight hyaluronan. Inhibition of induction by various compounds was used as a surrogate for inflammatory activity and confirmed by interleukin (IL)-10 ELISA. OPN was elevated in both the plasma (2.08 vs 1.19 ng/mL; P < .05) and the aortic wall homogenate (154.0 vs 38.3 ng/mL; P < .01) of AAAs compared to controls. On immunohistochemistry, OPN localized to the tunica media and VSMCs of the diseased aorta but was not visible in healthy aorta from multiorgan donors. Cigarette smoke extract was the most potent stimulator of OPN secretion in VSMCs and increased supernatant concentration by 2.5-fold and messenger RNA concentration by fourfold over control (P < .05). OPN additionally demonstrated an ability to inhibit the induction of IL-10-secreting TR1 lymphocytes, a depleted population in the AAA patient, from naïve precursors by half (P < .01; Fig). OPN is elevated in the plasma and aortic wall of patients with AAA and is secreted by the VSMCs of the tunica media. It is responsible for inhibition of TR1 cells, decreased IL-10 expression, and an overall proinflammatory environment leading to vessel breakdown and diameter growth. Therefore, inhibition of OPN activity could represent a potential first-in-man pharmaceutical treatment for AAA.