Velot Emilie, Haas Benjamin, Léonard Frédérique, Ernens Isabelle, Rolland-Turner Magali, Schwartz Chantal, Longrois Dan, Devaux Yvan, Wagner Daniel R
Laboratory of Cardiovascular Research, CRP-Santé, Luxembourg, Luxembourg.
Cardiovasc Res. 2008 Nov 1;80(2):246-54. doi: 10.1093/cvr/cvn201. Epub 2008 Jul 24.
Matrix metalloproteinase-9 (MMP-9) plays an important role in ventricular remodelling after acute myocardial infarction (MI). The cardioprotectant adenosine (Ado) may be involved in ventricular remodelling. We have shown that Ado inhibits the secretion of MMP-9 by human neutrophils. This study investigated the effect of Ado on MMP-9 production by human macrophages.
Cells used in this study were monocytes of healthy volunteers, a human monocyte cell line, and leukocytes from patients following MI. Monocytes were differentiated into macrophages and treated with Ado. Ado enhanced MMP-9 secretion by human macrophages in a time- and dose-dependent manner. Increasing the level of endogenous Ado by inhibition of Ado deaminase or Ado transferase also increased MMP-9 secretion. Ado enhanced MMP-9 production when macrophages were activated by hypoxia or Toll-like receptor-4 ligands such as lipopolysaccharide, hyaluronan, and heparan sulfate. The effect of Ado was replicated by the A3 agonist IB-MECA and inhibited by silencing the A3 receptor. Ado improved monocyte capacity to migrate through a matrix of gelatin B, and this effect was blocked by inhibition of MMP-9 activity. The chemotactic capacity of macrophages was reduced by Ado through a loss of expression of the monocyte chemotactic protein-1 receptor. Finally, MMP-9 expression was higher in blood cells from patients with acute MI compared with healthy volunteers.
Adenosine activates MMP-9 secretion by macrophages through its A3 receptor. The effect is in contrast to that observed in neutrophils, where Ado inhibits MMP-9 secretion by the A2a receptor. These observations may have important implications for therapeutic strategies targeting Ado receptors in the setting of MI.
基质金属蛋白酶-9（MMP-9）在急性心肌梗死（MI）后的心室重塑中起重要作用。心脏保护剂腺苷（Ado）可能参与心室重塑。我们已表明Ado可抑制人中性粒细胞分泌MMP-9。本研究调查了Ado对人巨噬细胞产生MMP-9的影响。
本研究使用的细胞为健康志愿者的单核细胞、人单核细胞系以及急性心肌梗死后患者的白细胞。单核细胞分化为巨噬细胞并接受Ado处理。Ado以时间和剂量依赖性方式增强人巨噬细胞分泌MMP-9。通过抑制腺苷脱氨酶或腺苷转移酶提高内源性Ado水平也会增加MMP-9分泌。当巨噬细胞被缺氧或Toll样受体-4配体（如脂多糖、透明质酸和硫酸乙酰肝素）激活时，Ado会增强MMP-9的产生。A3激动剂IB-MECA可复制Ado的作用，而沉默A3受体可抑制该作用。Ado提高了单核细胞穿过明胶B基质的迁移能力，且这种作用可被抑制MMP-9活性所阻断。Ado通过降低单核细胞趋化蛋白-1受体的表达来降低巨噬细胞的趋化能力。最后，与健康志愿者相比，急性心肌梗死患者血细胞中的MMP-9表达更高。
腺苷通过其A3受体激活巨噬细胞分泌MMP-9。该作用与在中性粒细胞中观察到的相反，在中性粒细胞中Ado通过A2a受体抑制MMP-9分泌。这些观察结果可能对急性心肌梗死背景下针对腺苷受体的治疗策略具有重要意义。
