Gu Dongsheng, Soepriatna Arvin H, Zhang Wenjun, Li Jun, Zhao Jenny, Zhang Xiaoli, Shu Xianhong, Wang Yongshi, Landis Benjamin J, Goergen Craig J, Xie Jingwu
Department of Pediatrics, Indiana University School of Medicine, Wells Center for Pediatric Research, 1040 W. Walnut Street., Indianapolis, IN, 46202, USA.
Purdue University Weldon School of Biomedical Engineering, 206 S. Martin Jischke Drive, Room 3025, West Lafayette, IN, 47907, USA.
Cell Biosci. 2023 Mar 2;13(1):43. doi: 10.1186/s13578-023-00980-1.
Fibrosis is a pathological wound healing process characterized by excessive extracellular matrix deposition, which interferes with normal organ function and contributes to ~ 45% of human mortality. Fibrosis develops in response to chronic injury in nearly all organs, but the a cascade of events leading to fibrosis remains unclear. While hedgehog (Hh) signaling activation has been associated with fibrosis in the lung, kidney, and skin, it is unknown whether hedgehog signaling activation is the cause or the consequence of fibrosis. We hypothesize that activation of hedgehog signaling is sufficient to drive fibrosis in mouse models.
In this study, we provide direct evidence to show that activation of Hh signaling via expression of activated smoothened, SmoM2, is sufficient to induce fibrosis in the vasculature and aortic valves. We showed that activated SmoM2 -induced fibrosis is associated with abnormal function of aortic valves and heart. The relevance of this mouse model to human health is reflected in our findings that elevated GLI expression is detected in 6 out of 11 aortic valves from patients with fibrotic aortic valves.
Our data show that activating hedgehog signaling is sufficient to drive fibrosis in mice, and this mouse model is relevant to human aortic valve stenosis.
纤维化是一种病理性伤口愈合过程，其特征是细胞外基质过度沉积，这会干扰正常器官功能，并导致约45%的人类死亡。几乎在所有器官中，纤维化都是对慢性损伤的反应，但导致纤维化的一系列事件仍不清楚。虽然刺猬（Hh）信号通路激活与肺、肾和皮肤的纤维化有关，但刺猬信号通路激活是纤维化的原因还是结果尚不清楚。我们假设刺猬信号通路激活足以在小鼠模型中驱动纤维化。
在本研究中，我们提供了直接证据表明，通过表达活化的 smoothened（SmoM2）激活Hh信号通路足以在血管和主动脉瓣中诱导纤维化。我们表明，活化的SmoM2诱导的纤维化与主动脉瓣和心脏的功能异常有关。我们的研究结果表明，在11例纤维化主动脉瓣患者的主动脉瓣中，有6例检测到GLI表达升高，这反映了该小鼠模型与人类健康的相关性。
我们的数据表明，激活刺猬信号通路足以在小鼠中驱动纤维化，并且该小鼠模型与人类主动脉瓣狭窄相关。
