Molkentin Jeffery D, Bugg Darrian, Ghearing Natasha, Dorn Lisa E, Kim Peter, Sargent Michelle A, Gunaje Jagadambika, Otsu Kinya, Davis Jennifer
From Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, OH (J.D.M., N.G., L.E.D., M.A.S.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, OH (J.D.M); Department of Bioengineering, University of Washington, Seattle (D.B., P.K., J.G. J.D.); and Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, United Kingdom (K.O.).
Circulation. 2017 Aug 8;136(6):549-561. doi: 10.1161/CIRCULATIONAHA.116.026238. Epub 2017 Mar 29.
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 p38α ( 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 allele was used to delete the p38α encoding gene specifically in cardiac fibroblasts or myofibroblasts with 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 mitogen-activated protein kinase kinase 6, a direct inducer of p38, were generated to investigate whether this pathway can directly drive myofibroblast formation and the cardiac fibrotic response.
In mice, loss of 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 . Transgenic mice with fibroblast-specific activation of mitogen-activated protein kinase kinase 6-p38 developed interstitial and perivascular fibrosis in the heart, lung, and kidney as a result of enhanced myofibroblast numbers. Mechanistic experiments show that p38 transduces cytokine and mechanical signals into myofibroblast differentiation through the transcription factor serum response factor and the signaling effector calcineurin.
These findings suggest that signals from diverse modes of injury converge on p38α mitogen-activated protein kinase 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.
在心脏中，急性损伤会引发纤维化愈合反应，产生富含胶原蛋白的瘢痕，这种瘢痕起初具有保护作用，但如果持续时间不当，会加重心脏病。纤维化过程由细胞因子、神经内分泌效应器和机械应变引发，这些因素会促使驻留的成纤维细胞分化为收缩性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p38α（基因）会影响心脏损伤反应，但其在体内协调程序性成纤维细胞分化和纤维化过程中的直接作用尚不清楚。
使用条件性等位基因，通过两种不同的他莫昔芬诱导型表达Cre重组酶的基因靶向小鼠品系，特异性删除心脏成纤维细胞或肌成纤维细胞中的p38α编码基因。对小鼠进行缺血性损伤或慢性神经体液刺激，并监测其存活率、心脏功能和纤维化重塑情况。相反，构建了成纤维细胞特异性过表达p38直接诱导剂活化丝裂原活化蛋白激酶激酶6的转基因小鼠，以研究该信号通路是否能直接驱动肌成纤维细胞形成和心脏纤维化反应。
在小鼠中，p38α缺失可阻止心脏成纤维细胞分化为肌成纤维细胞，并抑制缺血性损伤或慢性神经体液刺激后的纤维化。在缺失p38α的皮肤创伤模型中，也观察到了类似的肌成纤维细胞形成和愈合抑制现象。成纤维细胞特异性激活丝裂原活化蛋白激酶激酶6-p38的转基因小鼠，由于肌成纤维细胞数量增加，在心脏、肺和肾脏中出现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和信号效应器钙调神经磷酸酶，将细胞因子和机械信号转化为肌成纤维细胞分化。
这些发现表明，来自不同损伤模式的信号汇聚于成纤维细胞内的p38α丝裂原活化蛋白激酶，以调控体内的纤维化反应和肌成纤维细胞形成，提示p38抑制剂可能成为未来临床应用的一种新型治疗方法。
