Department of Cardiology, Kerckhoff Heart and Thorax Center, Benekestrasse 2-8, D-61231 Bad Nauheim, Germany.
Eur Heart J. 2012 Mar;33(5):595-605. doi: 10.1093/eurheartj/ehr434. Epub 2011 Nov 21.
Aortic stenosis causes cardiac hypertrophy and fibrosis, which often persists despite pressure unloading after aortic valve replacement. The persistence of myocardial fibrosis in particular leads to impaired cardiac function and increased mortality. We investigated whether granulocyte colony-stimulating factor (G-CSF) beneficially influences cardiac remodelling after pressure unloading.
Left ventricular hypertrophy was induced by transverse aortic constriction in C57bl6 mice followed by debanding after 8 weeks. This model closely mimics aortic stenosis and subsequent aortic valve replacement. After debanding, mice were treated with either G-CSF or saline injection. Granulocyte colony-stimulating factor treatment significantly improved systolic (ejection fraction 70.48 ± 1.17 vs. 58.41 ± 1.56%, P < 0.001) and diastolic (E/E' 26.0 ± 1.0 vs. 32.6 ± 0.8, P < 0.05) function. Furthermore, cardiac fibrosis was significantly reduced in G-CSF-treated mice (collagen-I area fraction 7.96 ± 0.47 vs. 11.64 ± 1.22%, P < 0.05; collagen-III area fraction 10.73 ± 0.99 vs. 18.46 ± 0.71%, P < 0.001). Direct effects of G-CSF on cardiac fibroblasts or a relevant transdifferentiation of mobilized bone marrow cells could be excluded. However, a considerable infiltration of neutrophils was observed in G-CSF-treated mice. This sterile inflammation was accompanied by a selective release of interleukin-1 β (IL-1β) in the absence of other proinflammatory cytokines. In vitro experiments confirmed an increased expression of IL-1β in neutrophils after G-CSF treatment. Interleukin-1β directly induced the expression of the gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 in cardiac fibroblasts thereby providing the regression of cardiac fibrosis.
Granulocyte colony-stimulating factor treatment improves the cardiac function and leads to the regression of myocardial fibrosis after pressure unloading. These findings reveal a previously unknown mechanism of fibrosis regression. Granulocyte colony-stimulating factor might be a potential pharmacological treatment approach for patients suffering from congestive heart failure after aortic valve replacement, although further basic research and clinical trials are required in order to prove beneficial effects of G-CSF in the human organism.
主动脉瓣狭窄导致心肌肥厚和纤维化，尽管主动脉瓣置换术后压力卸载，但这种情况通常仍会持续存在。特别是心肌纤维化的持续存在会导致心功能受损和死亡率增加。我们研究了粒细胞集落刺激因子（G-CSF）是否有益于压力卸载后心脏重塑。
通过在 C57bl6 小鼠的横主动脉缩窄诱导左心室肥厚，然后在 8 周后解带。该模型紧密模拟主动脉瓣狭窄和随后的主动脉瓣置换。解带后，小鼠接受 G-CSF 或生理盐水注射治疗。G-CSF 治疗显著改善了收缩功能（射血分数 70.48 ± 1.17%对 58.41 ± 1.56%，P < 0.001）和舒张功能（E/E' 26.0 ± 1.0 对 32.6 ± 0.8，P < 0.05）。此外，G-CSF 治疗组的心肌纤维化显著减少（胶原-I 面积分数 7.96 ± 0.47%对 11.64 ± 1.22%，P < 0.05；胶原-III 面积分数 10.73 ± 0.99%对 18.46 ± 0.71%，P < 0.001）。可以排除 G-CSF 对心肌成纤维细胞的直接作用或动员的骨髓细胞的相关转分化。然而，在 G-CSF 治疗的小鼠中观察到大量中性粒细胞浸润。这种无菌性炎症伴随着白细胞介素-1β（IL-1β）的选择性释放，而没有其他促炎细胞因子。体外实验证实 G-CSF 处理后中性粒细胞中 IL-1β 的表达增加。白细胞介素-1β 直接诱导心肌成纤维细胞中明胶酶基质金属蛋白酶-2（MMP-2）和 MMP-9 的表达，从而导致心肌纤维化的消退。
粒细胞集落刺激因子治疗可改善心脏功能，并导致压力卸载后心肌纤维化的消退。这些发现揭示了心肌纤维化消退的一种未知机制。粒细胞集落刺激因子可能是主动脉瓣置换术后充血性心力衰竭患者潜在的药物治疗方法，尽管需要进一步的基础研究和临床试验来证明 G-CSF 在人体中的有益作用。
