Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis

作者：Jeffery D. Molkentin, Darrian Bugg, Natasha Ghearing, Lisa E. Dorn, Peter S. Kim, Michelle A. Sargent, Jagadambika J. Gunaje, Kinya Otsu, Jennifer Davis · 发表于：Circulation · 年份：2017 · DOI：10.1161/circulationaha.116.026238 · 被引用次数：306 · 研究领域：Cardiac Fibrosis and Remodeling、Signaling Pathways in Disease、Melanoma and MAPK Pathways

Background: 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 ( 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. Methods: A conditional Mapk14 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. Results: 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 myofibrobl...