The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes. Total RNA was extracted from the hearts of 10 weeks old Junf/f (n=2) and Jun delta mu (n=2) mice using TRIzol Reagent.系统性高血压（Systemic hypertension）可增加心脏负荷，继而激活心脏内的信号网络，通过扩增肌节（sarcomere）介导心肌细胞生长（肥厚反应，hypertrophic response），以提升心肌收缩能力。然而，心脏负荷持续升高的状态下，可同时诱导心肌的适应性与失适应性生长。既往研究证实，AP-1转录因子家族（AP-1 transcription factor family）的两个成员junD与fra-1参与调控肥厚反应过程中的心脏生长。本研究聚焦于AP-1转录因子c-jun与c-fos在心脏生长中的功能。我们通过构建小鼠压力负荷诱导的心肌肥厚模型，并对心肌细胞（cardiomyocytes）内的Jun或Fos进行靶向敲除，结果显示：c-jun是适应性心肌肥厚所必需的转录因子，而c-fos在此过程中并非必需。c-jun可促进肌节蛋白的表达，并抑制细胞外基质蛋白的转录。心肌的收缩能力取决于肌节内主要粗细肌丝——肌球蛋白（myosin）与肌动蛋白（actin）的组织排布状态。与肌节相关蛋白表达下调的实验结果一致，Jun敲除的心肌细胞表现出肌节内肌丝排列紊乱以及肌动蛋白细胞骨架结构失衡。此外，经压力负荷造模的Jun敲除小鼠心脏会出现显著的纤维化（fibrosis）与心肌细胞凋亡，最终引发扩张型心肌病（dilated cardiomyopathy）。综上，在心脏负荷升高的应激条件下，c-jun而非c-fos是诱导心脏生长适应性转录程序的必需因子。本研究使用基因芯片（microarrays）筛选在心肌细胞缺失c-jun的情况下可能受到全局调控影响的特定基因。我们使用TRIzol试剂（TRIzol Reagent）从10周龄的Junf/f（n=2）与Jun delta mu（n=2）小鼠的心脏组织中提取总RNA。