Effects of Long-Term Type I Interferon on the Arterial Wall and Smooth Muscle Progenitor Cells Differentiation

Abstract

Objective-Patients with systemic lupus erythematosis are at risk for premature atherosclerosis and half of the patients with systemic lupus erythematosis have elevated type I interferon (IFN-I) levels. We hypothesized that IFN-I would induce premature atherosclerosis by increasing the number of smooth muscle progenitor cells (SMPC) in the bloodstream and promoting atherosclerotic lesions within the vasculature. Approach and Results-SMPC isolated from wild-type and IFN receptor knockout animals were cultured in medium±IFN-I.In vivo, we used electroporation to generate stable IFN-I expression for as long as 4 months. The number of SMPC was determined in mice that expressed IFN-I and in control mice and sections from the bifurcation of the abdominal aorta were analyzed 3 months after electroporation of an IFN-I expression plasmid or a control plasmid. Adding IFN-I to the media increased the number of cultured wild-type SMPC and increased mRNA for SM22, but had no effect on SMPC isolated from IFN receptor knockout mice. Our in vivo results demonstrated a positive relationship between the preatherosclerotic-like lesions and endothelial damage. Although, there were no significant differences in smooth muscle cell density or thickness of the medial layer between groups, the IFN-I-expressing mice had a significant increase in preatherosclerotic-like lesions and immature smooth muscle cells, cells that expressed CD34 and smooth muscle α-actin; but lacked smooth muscle myosin heavy chain. Conclusions-IFN-I seems to enhance SMPC number in vitro. In vivo IFN-I expression may maintain SMPC in an immature state. These immature smooth muscle cells could give rise to macrophages and eventually foam cells.

Reactive Oxygen Species Generation and Atherosclerosis

“…109 Recently, several publications in ATVB and other journals have demonstrated the progress in research on the role of stem/progenitor cells in atherosclerosis and oxidative stress. 13,[110][111][112][113][114] As mentioned earlier, oxidative stress response is a key event in the development of atherosclerosis, in which stem/progenitor cells sense the signal of ROS and other related species. One of the primary roles of ROS is to promote stem cell differentiation into SMCs important for both of neointimal formation after angioplasty and plaque stability.…”

The Plot Thickens Further for Type I Interferons in Atherosclerotic Disease

“…In human atherosclerotic lesions, characteristics of plaque instability associated with an IFN signature profile. 8 In their current study, Diao et al 9 now show that type I IFNs affect the functioning of smooth muscle progenitor cells (SMPCs) and hereby may affect atherosclerosis development. In their studies, they performed in vitro SMPC colony-forming assays using peripheral blood mononuclear cells from mice and show that type I IFNs promote SMPC colony formation.…”

Macrophages

“…73 The resulting inflammatory microenvironment may also feedback to promote increased alteration of SMCs. Type I interferons, major players in atherosclerosis, 74 maintain SMC progenitors in an immature state, 75 suggesting that they might facilitate SMC transition to phagocytic macrophage-like cells.…”