School of Animal Sciences, AgCenter, Louisiana State University, Baton Rouge, LA, USA.
Department of Biological Engineering, Louisiana State University, Baton Rouge, LA, USA.
J Mol Cell Cardiol. 2022 Oct;171:117-132. doi: 10.1016/j.yjmcc.2022.08.003. Epub 2022 Aug 22.
In response to myocardial infarction (MI), quiescent cardiac fibroblasts differentiate into myofibroblasts mediating tissue repair. One of the most widely accepted markers of myofibroblast differentiation is the expression of Acta2 which encodes smooth muscle alpha-actin (SMαA) that is assembled into stress fibers. However, the requirement of Acta2/SMαA in the myofibroblast differentiation of cardiac fibroblasts and its role in post-MI cardiac repair remained unknown. To answer these questions, we generated a tamoxifen-inducible cardiac fibroblast-specific Acta2 knockout mouse line. Surprisingly, mice that lacked Acta2 in cardiac fibroblasts had a normal post-MI survival rate. Moreover, Acta2 deletion did not affect the function or histology of infarcted hearts. No difference was detected in the proliferation, migration, or contractility between WT and Acta2-null cardiac myofibroblasts. Acta2-null cardiac myofibroblasts had a normal total filamentous actin level and total actin level. Acta2 deletion caused a significant compensatory increase in the transcription level of non-Acta2 actin isoforms, especially Actg2 and Acta1. Moreover, in myofibroblasts, the transcription levels of cytoplasmic actin isoforms were significantly higher than those of muscle actin isoforms. In addition, we found that myocardin-related transcription factor-A is critical for myofibroblast differentiation but is not required for the compensatory effects of non-Acta2 isoforms. In conclusion, the Acta2 deletion does not prevent the myofibroblast differentiation of cardiac fibroblasts or affect the post-MI cardiac repair, and the increased expression and stress fiber formation of non-SMαA actin isoforms and the functional redundancy between actin isoforms are able to compensate for the loss of Acta2 in cardiac myofibroblasts.
针对心肌梗死（MI），静止的心肌成纤维细胞分化为肌成纤维细胞，介导组织修复。肌成纤维细胞分化的最广泛接受的标志物之一是 Acta2 的表达，它编码平滑肌α-肌动蛋白（SMαA），该蛋白组装成应力纤维。然而，Acta2/SMαA 在心肌成纤维细胞的肌成纤维细胞分化中的作用及其在 MI 后心脏修复中的作用仍不清楚。为了回答这些问题，我们生成了一种可诱导的心肌成纤维细胞特异性 Acta2 敲除小鼠系。令人惊讶的是，缺乏心肌成纤维细胞 Acta2 的小鼠在 MI 后具有正常的存活率。此外，Acta2 缺失不影响梗死心脏的功能或组织学。WT 和 Acta2 缺失的心肌成纤维细胞之间在增殖、迁移或收缩性方面没有差异。Acta2 缺失的心肌成纤维细胞具有正常的总丝状肌动蛋白水平和总肌动蛋白水平。Acta2 缺失导致非 Acta2 肌动蛋白同工型的转录水平显著增加，尤其是 Actg2 和 Acta1。此外，在肌成纤维细胞中，细胞质肌动蛋白同工型的转录水平明显高于肌肉肌动蛋白同工型。此外，我们发现肌球蛋白相关转录因子 A 对于肌成纤维细胞分化是至关重要的，但对于非 Acta2 同工型的补偿作用是不必要的。总之，Acta2 缺失不会阻止心肌成纤维细胞的肌成纤维细胞分化，也不会影响 MI 后的心脏修复，非 SMαA 肌动蛋白同工型的表达增加和应力纤维形成以及肌动蛋白同工型之间的功能冗余能够补偿心肌成纤维细胞中 Acta2 的缺失。
