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.

译文

:尽管有希望的实验方法,迄今为止刺激患者的侧支动脉生长仍未成功。循环单核细胞参与侧支动脉的生长,这一过程也称为动脉生成。患者在对动脉阻塞的自然致动脉反应中表现出很大的异质性。我们假设循环的细胞转录组将提供机制的见解和刺激动脉生成的新治疗策略。在45例单支冠状动脉疾病患者中测量了侧支血流指数,将侧支反应者(侧支血流指数,> 0.21)和无反应者(侧支血流指数,<或1)分开。用脂多糖刺激分离的单核细胞或将其置于巨噬细胞培养物中20小时以模拟其在动脉生成过程中的表型。全基因组mRNA表达分析显示受刺激的单核细胞中244个差异表达的基因(校正后的P,<0.05)。干扰素(IFN)-β和一些与IFN相关的基因在来自无应答者的4种细胞表型中有3种显示出增加的mRNA水平。巨噬细胞基因表达与刺激的单核细胞相关,而静止的单核细胞和祖细胞没有显示差异的基因调控。在体外,IFN-β剂量依赖性抑制平滑肌细胞增殖。在鼠后肢模型中,股动脉结扎后7天测量的灌注显示,与对照组相比,经IFN-β治疗的小鼠的动脉生成减弱(治疗组与对照组:31.5 /-1.2%对41.9 /-1.9%灌注恢复,P <0.01) 。总之,用侧支血流指数测量的具有不同动脉生成反应的患者表现出受刺激的单核细胞转录组差异。无反应者显示IFN-β及其下游靶标的表达增加,并且IFN-β减弱了体外平滑肌细胞的增殖并阻碍了小鼠的动脉生成。 IFN-β信号的抑制可能作为刺激侧支动脉生长的一种新方法。

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