SPP1/osteopontin: a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?

Abstract

Degenerative ascending aortic aneurysm (AscAA) is a silent and potentially fatal disease characterized by excessive vascular inflammation and fibrosis. We aimed to characterize the cellular and molecular signature for the fibrotic type of endothelial mesenchymal transition (EndMT) that has previously been described in degenerative AscAA. Patients undergoing elective open-heart surgery for AscAA and/or aortic valve repair were recruited. Gene expression in the intima-media of the ascending aorta was measured in 22 patients with non-dilated and 24 with dilated aortas, and candidate genes were identified. Protein expression was assessed using immunohistochemistry. Interacting distal gene enhancer regions were identified using targeted chromosome conformation capture (HiCap) in untreated and LPS-treated THP1 cells, and the associated transcription factors were analyzed. Differential expression analysis identified SPP1 (osteopontin) as a key gene in the signature of fibrotic EndMT in patients with degenerative AscAA. The aortic intima-media expression of SPP1 correlated with the expression of inflammatory markers, the level of macrophage infiltration, and the aortic diameter. HiCap analysis, followed by transcription factor binding analysis, identified ETS1 as a potential regulator of SPP1 expression under inflammatory conditions. In conclusion, the present findings suggest that SPP1 may be involved in the development of the degenerative type of AscAA. Key messages In the original manuscript titled “SPP1/osteopontin, a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?” by David Freiholtz, Otto Bergman, Saliendra Pradhananga, Karin Lång, Flore-Anne Poujade, Carl Granath, Christian Olsson, Anders Franco-Cereceda, Pelin Sahlén, Per Eriksson, and Hanna M Björck, we present novel findings on regulatory factors on osteopontin (SPP1) expression in immune cells involved in degenerative ascending aortic aneurysms (AscAA). The central findings convey: SPP1 is a potential driver of the fibrotic endothelial-to-mesenchymal transition in AscAA. SPP1/osteopontin expression in AscAA is predominately by immune cells. ETS1 is a regulatory transcription factor of SPP1 expression in AscAA immune cells.

Lipoprotein retention and inflammation due to regurgitant blood flow as part of the natural history of degenerative ascending aortic aneurysms

“…Interestingly, non-canonical atherosclerotic processes have recently been described in the aneurysmal intima/media of patients with tricuspid aortic valves, signified by a pathological accumulation of macrophages and a disturbed lipid metabolism 5 . In our recent work, we could further enhance these findings by the identification infiltrating CD68+ immune cells expressing Secreted Phosphoprotein 1 that correlated with aortic dimensions and an augmented expression of inflammatory markers 6 . The mechanism enabling immune cells to migrate into to the sub-intimal space to facilitate inflammation initiation remains, however, unknown.…”

“…Indeed, OLR1 mRNA levels correlated with the expression of inflammatory markers, in both dilated and non-dilated aortas, and its expression was co-localized with infiltrating CD68+ cells. Interestingly, innate immune cells are prone to greater inflammatory activation by oxLDL 26 , which in the context of AscAA, may exacerbate downstream immune cell-associated degeneration 6 . Furthermore, a subcluster of OLR1+ macrophages were recently demonstrated in dissecting aortic tissue, that promoted formation of neutrophil extracellular traps 27 .…”

Comprehensive Analysis of Key Endoplasmic Reticulum Stress-Related Genes and Immune Infiltrates in Stanford Type A Aortic Dissection

“… 35 Previous research has linked SPP1 to abdominal and thoracic aneurysmal illness by upregulating matrix proteinases via NF-B, increasing tissue degradation. 36 , 37 A previous study showed that individuals with abdominal aortic aneurysm and AD had higher levels of SPP1 expression in the plasma and aortic wall than healthy controls. In AD patients, serum SPP1 levels correlate positively with MMP-2 levels.…”