Interferon-β Signaling Is Enhanced in Patients With Insufficient Coronary Collateral Artery Development and Inhibits Arteriogenesis in Mice

• Published in: Circulation research Vol. 102; no. 10; pp. 1286 - 1294
• Main Authors: Schirmer, Stephan H, Fledderus, Joost O, Bot, Pieter T.G, Moerland, Perry D, Hoefer, Imo E, Baan, Jan, Henriques, José P.S, van der Schaaf, René J, Vis, Marije M, Horrevoets, Anton J.G, Piek, Jan J, van Royen, Niels
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 23.05.2008; Lippincott
• Subjects: Aged; Animals; Apoptosis - genetics; Biological and medical sciences; Cells, Cultured; Collateral Circulation - drug effects; Collateral Circulation - physiology; Coronary Artery Disease - genetics; Coronary Artery Disease - metabolism; Coronary Artery Disease - physiopathology; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Genetic Variation; Hindlimb - blood supply; Humans; Interferon-beta - genetics; Interferon-beta - metabolism; Interferon-beta - pharmacology; Ischemia - genetics; Ischemia - metabolism; Ischemia - physiopathology; Lipopolysaccharides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - physiology; Mice; Middle Aged; Monocytes - cytology; Monocytes - drug effects; Monocytes - physiology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - physiology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Signal Transduction - physiology; Stem Cells - cytology; Stem Cells - physiology; Vertebrates: cardiovascular system; Human; monocytes; Monocyte; Cytokine; Rodentia; Coronary artery; stress testing; Gene expression; Stress; arteriogenesis; Collateral circulation; Signal transduction; Vertebrata; Mammalia; Mouse; Beta interferon; Development; Circulatory system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.108.171827

Stimulation of collateral artery growth in patients has been hitherto unsuccessful, despite promising experimental approaches. Circulating monocytes are involved in the growth of collateral arteries, a process also referred to as arteriogenesis. Patients show a large heterogeneity in their natural arteriogenic response on arterial obstruction. We hypothesized that circulating cell transcriptomes would provide mechanistic insights and new therapeutic strategies to stimulate arteriogenesis. Collateral flow index was measured in 45 patients with single-vessel coronary artery disease, separating collateral responders (collateral flow index, >0.21) and nonresponders (collateral flow index, ≤0.21). Isolated monocytes were stimulated with lipopolysaccharide or taken into macrophage culture for 20 hours to mimic their phenotype during arteriogenesis. Genome-wide mRNA expression analysis revealed 244 differentially expressed genes (adjusted P, <0.05) in stimulated monocytes. Interferon (IFN)-β and several IFN-related genes showed increased mRNA levels in 3 of 4 cellular phenotypes from nonresponders. Macrophage gene expression correlated with stimulated monocytes, whereas resting monocytes and progenitor cells did not display differential gene regulation. In vitro, IFN-β dose-dependently inhibited smooth muscle cell proliferation. In a murine hindlimb model, perfusion measured 7 days after femoral artery ligation showed attenuated arteriogenesis in IFN-β–treated mice compared with controls (treatment versus control31.5±1.2% versus 41.9±1.9% perfusion restoration, P<0.01). In conclusion, patients with differing arteriogenic response as measured with collateral flow index display differential transcriptomes of stimulated monocytes. Nonresponders show increased expression of IFN-β and its downstream targets, and IFN-β attenuates proliferation of smooth muscle cells in vitro and hampers arteriogenesis in mice. Inhibition of IFN-β signaling may serve as a novel approach for the stimulation of collateral artery growth.