Objective: Previous in vitro and animal studies have suggested that osteopontin (OPN), an inflammatory extracellular matrix protein, is involved in the formation and growth of abdominal aortic aneurysms (AAAs). However, the mechanism by which this occurs continues to be nebulous. The relationship between OPN and inflammation-suppressing lymphocytes present in the human AAA condition was investigated and presented herein. Methods: Serum OPN concentrations were measured in healthy, 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 aortic tissue collected from multiorgan donors and AAA patients undergoing open surgical repair. Vascular smooth muscle cells (VSMCs) were exposed to various inflammatory mediators, and OPN expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction and ELISA. The inflammatory nature of OPN and the aortic wall was determined using a TR1 suppressor cell induction assay as a surrogate and characterized by ELISA and fluorescence-activated cell sorting. Results: OPN was found to be elevated in both the plasma and aortic homogenate of AAA patients compared with controls. On immunohistochemistry, OPN localized to the tunica media of the diseased aorta but was minimally expressed in healthy aorta. In vitro, cigarette smoke extract was the most potent stimulator of OPN secretion by VSMCs and increased both messenger RNA and supernatant concentrations. OPN demonstrated an ability to inhibit the induction of interleukin 10-secreting TR1 lymphocytes, a depleted population in the AAA patient, from naive precursors. Last, neutralizing receptor targets of OPN in the setting of AAA homogenate coincubation abrogated the inhibition of TR1 induction. Conclusions: OPN, secreted by the VSMCs of the tunica media, is elevated in the circulating plasma and aortic wall of patients with AAA. It can inhibit the induction of the TR1 suppressor cell, leading to an overall proinflammatory state contributing to progressive aortic wall breakdown and dilation. Clinical Relevance: Little is known about the initiating event of abdominal aortic aneurysm formation. However, the early histology of the ectatic aorta is characterized by massive infiltration of mononuclear cells and elaboration of matrix metalloproteinases, collagenases, and elastases. This runaway inflammatory response directly leads to extracellular matrix degradation and loss of aortic integrity. In this study, we report elevations of osteopontin (OPN), an extracellular matrix glycoprotein associated with inflammation in other pathologic processes. In addition, OPN demonstrated an ability to inhibit the expression of the TR1 lymphocyte, a potent suppressor of inflammation. Therefore, we argue that accumulation of OPN in the aortic wall may be a potent driver for abdominal aortic aneurysm propagation.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine