Cardiomyocyte A Disintegrin And Metalloproteinase 17 (ADAM17) Is Essential in Post-Myocardial Infarction Repair by Regulating Angiogenesis
Cardiomyocyte A Disintegrin And Metalloproteinase 17 (ADAM17) Is Essential in Post-Myocardial Infarction Repair by Regulating Angiogenesis
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DOI：
10.1161/circheartfailure.114.002029
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发表时间：
2015-09-01
影响因子：
9.7
通讯作者：
Kassiri, Zamaneh
中科院分区：
文献类型：
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作者：
Fan, Dong;Takawale, Abhijit;Kassiri, Zamaneh
背景去整合素和金属蛋白酶17（ADAM 17）是一种膜结合酶，介导许多膜结合分子的脱落，从而调节多种细胞反应。方法和结果心肌细胞特异性ADAM 17基因敲除小鼠（ADAM 17（flox/flox）/-MHC-Cre; f/f/Cre）和平行对照小鼠（ADAM 17（flox/flox）; f/f）通过结扎左前降支造成心肌梗死。MI后，与平行的f/f-MI小鼠相比，f/f/Cre小鼠的存活率降低，心脏破裂率更高，左心室扩张更严重，射血分数抑制。离体缺血性损伤（离体心脏）导致两种基因型的恢复相当。与f/f-MI小鼠相比，f/f/Cre-MI小鼠梗死区的心肌血管密度（荧光标记凝集素灌注和CD 31免疫荧光染色）显著降低。血管内皮生长因子受体2（VEGFR 2）的激活，其mRNA和总蛋白水平在ADAM 17敲除小鼠的梗死心肌中降低。在共培养的心肌细胞-成纤维细胞中证实了ADAM 17对VEGFR 2的转录调节，因为缺血诱导的VEGFR 2表达被ADAM 17-siRNA阻断。同时，ADAM 17-siRNA没有改变条件培养基中VEGF（A）的生物利用度。ADAM 17敲除小鼠（f/f/Cre-MI）在梗死心肌中表现出核因子B活化（DNA结合）降低，这可能是这些心脏中VEGF 2表达受抑制的基础。MI后，炎症反应没有改变ADAM 17 downregulation.Conclusions心肌细胞ADAM 17在MI后恢复的关键作用，通过调节VEGFR 2转录和血管生成，从而限制左心室扩张和功能障碍。因此，在生理范围内，ADAM 17上调可以在缺血性心肌病中提供保护作用。
Background A disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound enzyme that mediates shedding of many membrane-bound molecules, thereby regulating multiple cellular responses. We investigated the role of cardiomyocyte ADAM17 in myocardial infarction (MI).Methods and Results Cardiomyocyte-specific ADAM17 knockdown mice (ADAM17(flox/flox)/-MHC-Cre; f/f/Cre) and parallel controls (ADAM17(flox/flox); f/f) were subjected to MI by ligation of the left anterior descending artery. Post MI, f/f/Cre mice showed compromised survival, higher rates of cardiac rupture, more severe left ventricular dilation, and suppressed ejection fraction compared with parallel f/f-MI mice. Ex vivo ischemic injury (isolated hearts) resulted in comparable recovery in both genotypes. Myocardial vascular density (fluorescent-labeled lectin perfusion and CD31 immunofluorescence staining) was significantly lower in the infarct areas of f/f/Cre-MI compared with f/f-MI mice. Activation of vascular endothelial growth factor receptor 2 (VEGFR2), its mRNA, and total protein levels were reduced in infarcted myocardium in ADAM17 knockdown mice. Transcriptional regulation of VEGFR2 by ADAM17 was confirmed in cocultured cardiomyocyte-fibroblast as ischemia-induced VEGFR2 expression was blocked by ADAM17-siRNA. Meanwhile, ADAM17-siRNA did not alter VEGF(A) bioavailability in the conditioned media. ADAM17 knockdown mice (f/f/Cre-MI) exhibited reduced nuclear factor-B activation (DNA binding) in the infarcted myocardium, which could underlie the suppressed VEGFR2 expression in these hearts. Post MI, inflammatory response was not altered by ADAM17 downregulation.Conclusions This study highlights the key role of cardiomyocyte ADAM17 in post-MI recovery by regulating VEGFR2 transcription and angiogenesis, thereby limiting left ventricular dilation and dysfunction. Therefore, ADAM17 upregulation, within the physiological range, could provide protective effects in ischemic cardiomyopathy.