FosB Regulates Stretch-Induced Expression of Extracellular Matrix Proteins in Smooth Muscle
FosB Regulates Stretch-Induced Expression of Extracellular Matrix Proteins in Smooth Muscle
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DOI：
10.1016/j.ajpath.2011.08.034
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发表时间：
2011-12-01
影响因子：
6
通讯作者：
Adam, Rosalyn M.
中科院分区：
文献类型：
--
作者：
Ramachandran, Aruna;Gong, Edward M.;Adam, Rosalyn M.
富含平滑肌的中空器官中的纤维增殖重塑与异常细胞外基质（ECM）的产生有关。尽管机械刺激调节 ECM 蛋白表达，但这一过程的转录介质仍不清楚。之前，我们认为 AP-1 是平滑肌细胞 (SMC) 机械转导的介质；然而，其在拉伸诱导的 ECM 调节中的作用尚未被探索。在此，我们确定了 AP-1 亚基 FosB 在 SMC 拉伸诱导的 ECM 表达中的新作用。体外拉伸刺激 SMC 后，AP-1 的 DNA 结合活性增加。与 c-Jun 和 c-fos 不同，c-Jun 和 c-fos 也被 SMC 有丝分裂原血小板衍生生长因子激活，而 FosB 仅通过拉伸激活。 FosB 沉默减弱了促纤维化因子生腱蛋白 C (TNC) 和结缔组织生长因子 (CTGF) 的表达，而类似于 FosB 的 Jun 强制表达则刺激了 TNC 和 CTGF 启动子活性。染色质免疫沉淀显示 TNC 和 CTGF 启动子处 AP-1 富集。体内膀胱扩张增强了 c-jun 和 FosB 的核定位。最后，野生型小鼠膀胱逼尿肌平滑肌中扩张诱导的 TNC 和 CTGF 表达在 FosB 缺失小鼠中显着减弱。总之，这些发现确定 FosB 是平滑肌 ECM 产生的机械敏感调节剂。 (Am J Pathol 2011, 179:2977-2989; DOI: 10.1016/j.ajpath.2011.08.034)
Fibroproliferative remodeling in smooth muscle rich hollow organs is associated with aberrant extracellular matrix (ECM) production. Although mechanical stimuli regulate ECM protein expression, the transcriptional mediators of this process remain poorly defined. Previously, we implicated AP-1 as a mediator of smooth muscle cell (SMC) mechanotransduction; however, its role in stretch-induced ECM regulation has not been explored. Herein, we identify a novel role for the AP-1 subunit FosB in stretch-induced ECM expression in SMCs. The DNA-binding activity of AP-1 increased after stretch stimulation of SMCs in vitro. In contrast to c-Jun and c-fos, which are also activated by the SMC mitogen platelet-derived growth factor, FosB was only activated by stretch. FosB silencing attenuated the expression of the profibrotic factors tenascin C (TNC) and connective tissue growth factor (CTGF), whereas forced expression of Jun similar to FosB stimulated TNC and CTGF promoter activity. Chromatin immunoprecipitation revealed enrichment of AP-1 at the TNC and CTGF promoters. Bladder distension in vivo enhanced nuclear localization of c-jun and FosB. Finally, the distension-induced expression of TNC and CTGF in the detrusor smooth muscle of bladders from wild-type mice was significantly attenuated in FosB-null mice. Together, these findings identify FosB as a mechanosensitive regulator of ECM production in smooth muscle. (Am J Pathol 2011, 179:2977-2989; DOI: 10.1016/j.ajpath.2011.08.034)