Interferon-beta signaling is enhanced in patients with insufficient coronary collateral artery development and inhibits arteriogenesis in mice.
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, < or 1). 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)-beta 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-beta 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-beta-treated mice compared with controls (treatment versus control: 31.5+/-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-beta and its downstream targets, and IFN-beta attenuates proliferation of smooth muscle cells in vitro and hampers arteriogenesis in mice. Inhibition of IFN-beta signaling may serve as a novel approach for the stimulation of collateral artery growth.
Schirmer
Stephan H
SH
Department of Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. stephan.schirmer@uks.eu
Fledderus
Joost O
JO
Bot
Pieter T G
PT
Moerland
Perry D
PD
Hoefer
Imo E
IE
Baan
Jan
J
Henriques
José P S
JP
van der Schaaf
René J
RJ
Vis
Marije M
MM
Horrevoets
Anton J G
AJ
Piek
Jan J
JJ
van Royen
Niels
N
D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D003097:Collateral Circulation / Q000187:drug effects / Q000502:physiology*; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D014644:Genetic Variation; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D008070:Lipopolysaccharides; D016899:Interferon-beta