Interferon-α promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis

• Published in: Blood Vol. 110; no. 8; pp. 2907 - 2915
• Main Authors: Denny, Michael F., Thacker, Seth, Mehta, Hemal, Somers, Emily C., Dodick, Todd, Barrat, Franck J., McCune, W. Joseph, Kaplan, Mariana J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.10.2007; The Americain Society of Hematology; American Society of Hematology
• Series: Hemostasis, Thrombosis, and Vascular Biology
• Subjects: Adult; Apoptosis - physiology; Atherosclerosis - etiology; Biological and medical sciences; Cell Differentiation - physiology; Endothelial Cells - metabolism; Female; Hematologic and hematopoietic diseases; Hemostasis, Thrombosis, and Vascular Biology; Humans; Interferon-alpha - metabolism; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - physiopathology; Male; Medical sciences; Neovascularization, Pathologic - physiopathology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Stem Cells - metabolism; Premature; Immunopathology; Connective tissue disease; Skin disease; Hematology; Alpha interferon; Autoimmune disease; Cardiovascular disease; Vascular disease; Systemic lupus erythematosus; Systemic disease; Atherosclerosis; Vasculogenesis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-05-089086

Individuals with systemic lupus erythematosus (SLE) have a striking increase in premature atherosclerosis of unclear etiology. Accelerated endothelial cell apoptosis occurs in SLE and correlates with endothelial dysfunction. Endothelial progenitor cells (EPCs) and myelomonocytic circulating angiogenic cells (CACs) are crucial in blood vessel repair after vascular damage, and decreased levels or abnormal function of EPCs/CACs are established atherosclerosis risk factors. We investigated if vascular repair is impaired in SLE. We report that SLE patients display abnormal phenotype and function of EPCs/CACs. These abnormalities are characterized by significant decreases in the number of circulating EPCs (310 ± 50 EPCs/mL of blood in SLE versus 639 ± 102 in controls) and significant impairments in the capacity of EPCs/CACs to differentiate into mature ECs and synthesize adequate levels of the proangiogenic molecules vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF). These abnormalities are triggered by interferon-α (IFN-α), which induces EPC and CAC apoptosis and skews myeloid cells toward nonangiogenic phenotypes. Lupus EPCs/CACs have increased IFN-α expression and their supernatants promote higher induction of IFN-inducible genes. Importantly, neutralization of IFN pathways restores a normal EPC/CAC phenotype in lupus. SLE is characterized by an imbalance between endothelial cell damage and repair triggered by type I IFNs, which might promote accelerated atherosclerosis.