The TNNI3 p.R186Q mutation is responsible for hypertrophic cardiomyopathy via promoting FASN-stimulated abnormal fatty acid metabolism
The TNNI3 p.R186Q mutation is responsible for hypertrophic cardiomyopathy via promoting FASN-stimulated abnormal fatty acid metabolism
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TNNI3 p.R186Q 突变通过促进 FASN 刺激的异常脂肪酸代谢而导致肥厚型心肌病
DOI：
10.20517/jca.2022.29
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
hui Zhou
中科院分区：
文献类型：
--
作者：
yang Shen;rong Wan;hui Zhou
前言：TNNI3基因编码肌钙蛋白I(CTnI)的蛋白，cTnI是肌节的抑制亚基。该基因突变占肥厚型心肌病(HCM)的3%，其分子机制复杂。最近发现，脂质代谢参与了肥厚性心肌病的发病。目的：探讨肥厚性心肌病热点突变TNNI3p.R186Q的发病机制是否与脂代谢异常有关。方法和结果：采用CRISPR/Cas9技术建立了携带Tnni3p.R186Q纯合子突变的KI小鼠模型(Tnni3R186Q/R186Q)，并成功构建了典型的心肌病表型。同样，用带有TNNI3p.R186Q突变的突变质粒转染新生大鼠心肌细胞(NRCM)也表现出同样的现象。对Tnni3R186Q/R186Q小鼠的相关功能和分子机制进行了深入的实验研究，发现Tnni3R186Q/R186Q小鼠体内、外脂肪酸代谢异常是由依赖表皮生长因子受体(EGFR)的高表达脂肪酸合成酶(FASN)激活所致。生物信息学、Co-IP和GST-Pull-down分析表明，TNNI3 p.R186Q突变破坏了EGFR与cTnI的直接结合。结论：本研究成功培育出具有典型心肌肥大表型的Tnni3R186Q/R186Q小鼠。我们证明了TnNI3p.R186Q突变可以通过EGFR和cTnI的解离来诱导肥厚性心肌梗死，进而导致EGFR依赖的FASN表达增加和脂代谢异常。
Introduction: The TNNI3 gene encodes the protein of cardiac troponin I (cTnI), which is an inhibitory subunit of sarcomeres. Mutations in this gene account for 3% of hypertrophic cardiomyopathy (HCM) and the molecular mechanism is complex. Recently, lipid metabolism has been revealed to be involved in HCM. Aim: The purpose of this work is to identify whether the pathological mechanism of the hotspot mutation TNNI3 p.R186Q in HCM is related to abnormal lipid metabolism. Methods and Results: A knock-in (KI) mouse model carrying the Tnni3 p.R186Q homozygous mutation (Tnni3R186Q/R186Q) was novelty generated by CRISPR/Cas9 technology and successfully constructed a typical phenotype of cardiac-myopathy. Likewise, neonatal rat cardiomyocytes (NRCMs) transfected with a mutant plasmid with the TNNI3 p.R186Q mutation showed the same phenomenon. In-depth experiments on related functions and molecular mechanisms were conducted, and Tnni3R186Q/R186Q mice exhibited abnormal fatty acid metabolism, which was induced by the activation of epidermal growth factor receptor (EGFR)-dependent high expression of fatty acid synthase (FASN) in vivo and in vitro. Specifically, the direct binding of EGFR and cTnI was destroyed by TNNI3 p.R186Q mutation, as observed through bioinformatics, Co-IP and GST-pull down analysis. Conclusion: In the present study, we successfully engineered Tnni3R186Q/R186Q mice with the typical phenotype of myocardial hypertrophy. We demonstrated that the TNNI3 p.R186Q mutation could induce HCM by the dissociation of EGFR and cTnI, which further led to EGFR-dependent increased expression of FASN and abnormal lipid metabolism.
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