IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice
IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice
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DOI：
10.1152/ajpheart.01285.2008
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发表时间：
2009-07-01
影响因子：
4.8
通讯作者：
Larson, Douglas F.
中科院分区：
文献类型：
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作者：
Yu, Qianli;Vazquez, Randy;Larson, Douglas F.
于强，Vazquez R, Khojeini EV, Patel C, Venkataramani R, Larson DF。IL-18诱导骨桥蛋白介导小鼠心脏纤维化和舒张功能障碍。[J] .中国生物医学工程学报，2009,31(2):776 - 785。2009年5月8日首次发表；doi: 10.1152 / ajpheart.01285.2008。骨桥蛋白（OPN）是细胞外基质的关键成分，与组织重塑过程中的纤维化过程有关。OPN和细胞因子白细胞介素(IL)-18已被证明在一系列人类心脏疾病中过度表达。在本研究中，我们确定了IL-18在调节心脏OPN表达以及随后的间质纤维化和舒张功能障碍中的作用。我们在左心室压力和容量过载的小鼠模型中证实了IL-18、OPN表达和间质纤维化的平行增加。给药2周后，外源性重组(r)IL-18增加了心脏OPN表达、间质纤维化和舒张功能障碍。选择性toll样受体（TLR）9激动剂刺激辅助性T (Th)1淋巴细胞表型诱导心脏IL-18和OPN表达，这与心脏纤维胶原浓度增加和间质纤维化导致舒张功能障碍有关。il -18诱导心肌成纤维细胞原代培养中OPN的表达和蛋白水平。tlr9刺激T淋巴细胞培养的条件培养基诱导心肌成纤维细胞中IL-18和OPN的表达，而用中和抗体阻断IL-18受体可消除OPN表达的增加。此外，转录因子干扰素调节因子（IRF）1或IRF1小干扰RNA （siRNA）的突变导致心脏成纤维细胞中IL-18和OPN的表达降低。压力过载时，与野生型相比，irf1突变小鼠心脏组织中IL-18和OPN表达下调，心脏纤维化发展减少，左心室功能增加。这些结果为诱导IL-18调节opn介导的心脏纤维化和舒张功能障碍提供了直接证据。
Yu Q, Vazquez R, Khojeini EV, Patel C, Venkataramani R, Larson DF. IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. Am J Physiol Heart Circ Physiol 297: H76-H85, 2009. First published May 8, 2009; doi:10.1152/ajpheart.01285.2008.-Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction.