MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis.
MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis.
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心脏成纤维细胞中 MYBPC3 的缺乏会驱动其激活并导致纤维化。
DOI：
10.1038/s41419-022-05403-6
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发表时间：
2022-11-10
影响因子：
9
通讯作者：
Tang, Xiaochun
中科院分区：
文献类型：
--
作者：
Zou, Xiaodong;Ouyang, Hongsheng;Lin, Feng;Zhang, Huanyu;Yang, Yang;Pang, Daxin;Han, Renzhi;Tang, Xiaochun
MYBPC3基因编码心肌肌球蛋白结合蛋白C(cMyBP-C)的基因突变是肥厚型心肌病(HCM)最常见的原因。心肌纤维化(MF)在肥厚性心肌病的发生发展中起着重要作用。然而，突变MYBPC3诱导MF的机制还不是很清楚。在这项研究中，我们利用胞嘧啶碱基编辑建立了一个R495Q突变猪模型，并在这些突变猪出生后不久观察到了一种早发性MF。出乎意料的是，我们发现心脏特异的MYBPC3基因实际上在不同物种的心脏成纤维细胞以及NIH3T3成纤维细胞中都在转录和蛋白水平上表达。CRISPR介导的MYBPC3基因在NIH3T3成纤维细胞中的破坏激活了核因子κB(NF-κB)信号通路，使转化生长因子-β(TGFR-β1)等促炎基因表达增加。转化生长因子-β-1上调可促进低氧诱导因子-1亚单位α及其下游糖酵解靶点α的表达。因此，增强的有氧糖酵解和较高的ATP生物合成速率加速了心脏成纤维细胞的激活，促进了肥厚性心肌病的发展。这项工作揭示了MYBPC3在维持心脏成纤维细胞动态平衡方面的内在作用，这些细胞中MYBPC3的破坏参与了HCM的发病机制。
Genetic mutations in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common cause of hypertrophic cardiomyopathy (HCM). Myocardial fibrosis (MF) plays a critical role in the development of HCM. However, the mechanism for mutant MYBPC3-induced MF is not well defined. In this study, we developed a R495Q mutant pig model using cytosine base editing and observed an early-onset MF in these mutant pigs shortly after birth. Unexpectedly, we found that the “cardiac-specific” MYBPC3 gene was actually expressed in cardiac fibroblasts from different species as well as NIH3T3 fibroblasts at the transcription and protein levels. CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated nuclear factor κB (NF-κB) signaling pathway, which increased the expression of transforming growth factor beta (TGF-β1) and other pro-inflammatory genes. The upregulation of TGF-β1 promoted the expression of hypoxia-inducible factor-1 subunit α (HIF-1α) and its downstream targets involved in glycolysis such as GLUT1, PFK, and LDHA. Consequently, the enhanced aerobic glycolysis with higher rate of ATP biosynthesis accelerated the activation of cardiac fibroblasts, contributing to the development of HCM. This work reveals an intrinsic role of MYBPC3 in maintaining cardiac fibroblast homeostasis and disruption of MYBPC3 in these cells contributes to the disease pathogenesis of HCM.
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