Bigger-Allen Alexander, Gheinani Ali Hashemi, Adam Rosalyn M
Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.
Biological & Biomedical Sciences Program, Division of Medical Sciences, Harvard Medical School, Boston, MA.
bioRxiv. 2023 Nov 14:2023.11.14.567076. doi: 10.1101/2023.11.14.567076.
Injury to contractile organs such as the heart, vasculature, urinary bladder and gut can stimulate a pathological response that results in loss of normal contractility. PDGF and TGFβ are among the most well studied initiators of the injury response and have been shown to induce aberrant contraction in mechanically active cells of hollow organs including smooth muscle cells (SMC) and fibroblasts. However the mechanisms driving contractile alterations downstream of PDGF and TGFβ in SMC and fibroblasts are incompletely understood, limiting therapeutic interventions. To identify potential molecular targets, we have leveraged the analysis of publicly available data, comparing transcriptomic changes in mechanically active cells stimulated with PDGF and TGFβ and identified a shared molecular profile regulated by MYC and members of the AP-1 transcription factor complex. We also analyzed data sets from SMC and fibroblasts treated in the presence or absence of the MYC inhibitor JQ1. This analysis revealed a unique set of cytoskeleton-associated genes that were sensitive to MYC inhibition. JQ1 was also able to attenuate TGFβ and PDGF induced changes to the cytoskeleton and contraction of smooth muscle cells and fibroblasts . These findings identify MYC as a key driver of aberrant cytoskeletal and contractile changes in fibroblasts and SMC, and suggest that JQ1 could be used to restore normal contractile function in hollow organs.
对心脏、血管、膀胱和肠道等收缩器官的损伤会引发一种病理反应，导致正常收缩功能丧失。血小板衍生生长因子（PDGF）和转化生长因子β（TGFβ）是损伤反应中研究最为深入的启动因子，已被证明能在包括平滑肌细胞（SMC）和成纤维细胞在内的中空器官的机械活性细胞中诱导异常收缩。然而，PDGF和TGFβ下游驱动SMC和成纤维细胞收缩改变的机制尚未完全明确，这限制了治疗干预措施。为了确定潜在的分子靶点，我们利用公开可用数据进行分析，比较了用PDGF和TGFβ刺激的机械活性细胞中的转录组变化，并确定了由MYC和活化蛋白-1（AP-1）转录因子复合物成员调控的共同分子谱。我们还分析了在有或没有MYC抑制剂JQ1的情况下处理的SMC和成纤维细胞的数据集。该分析揭示了一组对MYC抑制敏感的独特细胞骨架相关基因。JQ1还能够减弱TGFβ和PDGF诱导的细胞骨架变化以及平滑肌细胞和成纤维细胞的收缩。这些发现确定MYC是成纤维细胞和SMC中异常细胞骨架和收缩变化的关键驱动因素，并表明JQ1可用于恢复中空器官的正常收缩功能。
