Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis.
Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis.
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DOI：
10.1161/circulationaha.116.026238
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发表时间：
2017-08-08
期刊：
影响因子：
37.8
通讯作者：
Davis J
中科院分区：
文献类型：
--
作者：
Molkentin JD;Bugg D;Ghearing N;Dorn LE;Kim P;Sargent MA;Gunaje J;Otsu K;Davis J
在心脏中，急性损伤诱导纤维化愈合反应，产生富含胶原蛋白的瘢痕，其最初是保护性的，但如果不适当地持续，则可能使心脏病恶化。纤维化过程是由细胞因子、神经内分泌效应物和机械应变引发的，这些细胞因子、神经内分泌效应物和机械应变促进驻留的成纤维细胞分化成可收缩的和产生细胞外基质的肌成纤维细胞。已知丝裂原活化蛋白激酶（MAPK）p38α（Mapk 14基因）影响心脏损伤反应，但其在体内协调程序性成纤维细胞分化和纤维化中的直接作用尚不清楚。使用2种不同的他莫昔芬诱导型Cre重组酶表达基因靶向小鼠系，在心脏成纤维细胞或肌成纤维细胞中使用条件性Mapk 14等位基因特异性缺失p38α编码基因。使小鼠经受缺血性损伤或慢性神经体液刺激，并监测存活率、心脏功能和纤维化重塑。相反，产生了成纤维细胞特异性转基因过表达活化的MAPK激酶6（MKK 6）（p38的直接诱导物）的小鼠，以研究该途径是否可以直接驱动肌成纤维细胞形成和心脏纤维化反应。在小鼠中，Mapk 14的缺失阻断了心脏成纤维细胞分化为肌成纤维细胞，并随后阻断了响应于缺血性损伤或慢性神经体液刺激的纤维化。在缺失Mapk 14的皮肤创伤模型中也观察到类似的肌成纤维细胞形成和愈合抑制。由于肌成纤维细胞数量增加，具有成纤维细胞特异性激活MKK 6-p38的转基因小鼠在心脏、肺和肾脏中发展了间质和血管周围纤维化。机制实验表明，p38通过转录因子血清反应因子（SRF）和信号传导效应钙调神经磷酸酶将细胞因子和机械信号转导到肌成纤维细胞分化中。这些发现表明，来自不同损伤模式的信号汇聚在成纤维细胞内的p38α MAPK上，以编程体内纤维化反应和肌成纤维细胞形成，这表明p38抑制剂的新治疗方法可用于未来的临床应用。
In the heart acute injury induces a fibrotic healing response that generates collagen rich scarring that is at first protective but if inappropriately sustained can worsen heart disease. The fibrotic process is initiated by cytokines, neuroendocrine effectors and mechanical strain that promote resident fibroblast differentiation into contractile and extracellular matrix producing myofibroblasts. The mitogen-activated protein kinase (MAPK) p38α (Mapk14 gene) is known to influence the cardiac injury response, but its direct role in orchestrating programmed fibroblast differentiation and fibrosis in vivo is unknown. A conditional Mapk14 allele was used to delete the p38α encoding gene specifically in cardiac fibroblasts or myofibroblasts using 2 different tamoxifen-inducible Cre recombinase expressing gene-targeted mouse lines. Mice were subjected to ischemic injury or chronic neurohumoral stimulation and monitored for survival, cardiac function and fibrotic remodeling. Antithetically, mice with fibroblast-specific transgenic overexpression of activated MAPK kinase 6 (MKK6), a direct inducer of p38, were generated to investigate if this pathway can directly drive myofibroblast formation and the cardiac fibrotic response. In mice loss of Mapk14 blocked cardiac fibroblast differentiation into myofibroblasts and ensuing fibrosis in response to ischemic injury or chronic neurohumoral stimulation. A similar inhibition of myofibroblast formation and healing was also observed in a dermal wounding model with deletion of Mapk14. Transgenic mice with fibroblast-specific activation of MKK6-p38 developed interstitial and perivascular fibrosis in the heart, lung and kidney due to enhanced myofibroblast numbers. Mechanistic experiments show that p38 transduces cytokine and mechanical signals into myofibroblast differentiation through the transcription factor serum-response factor (SRF) and the signaling effector calcineurin. These findings suggest that signals from diverse modes of injury converge on p38α MAPK within the fibroblast to program the fibrotic response and myofibroblast formation in vivo, suggesting a novel therapeutic approach with p38 inhibitors for future clinical application.