心脏代谢重构是心肌肥厚的重要病理生理改变，与心力衰竭的发生紧密相关，但其调控机制尚不清楚。我们前期转录组测序筛选出小鼠主动脉缩窄致肥厚心脏中代谢相关转录因子ATF4显著上调，预实验证实ATF4蛋白也明显增加，心肌细胞特异性Atf4敲除则抑制代偿性心肌肥厚并加快心功能恶化，体外培养的心肌细胞敲低Atf4也抑制其肥大。转录组测序显示心肌细胞Atf4敲除显著下调糖酵解调控酶PFK2的表达，后者产物是糖酵解限速酶PFK1的强激活剂，与此一致Seahorse检测证实心肌细胞Atf4敲低显著抑制糖酵解。生物信息学提示Pfk2启动子区具有ATF4强结合位点，因此我们推测ATF4上调PFK2增强心肌细胞糖酵解，在心肌肥厚中起重要作用。本项目拟应用心肌细胞特异性Atf4敲除小鼠，结合转录组学、非靶向代谢组学、ChIP等技术，将首次阐明心肌细胞ATF4在心肌肥厚代谢重构中的作用及机制，为临床转化研究奠定基础。

Cardiometabolic remodeling is an important pathophysiological change of cardiac hypertrophy, and is closely related to the occurrence of heart failure, but its regulatory mechanism is unclear. Our previous transcriptome sequencing screened out a remarkably upregulated metabolism-related transcription factor, ATF4, in the hearts from mice with transverse aortic constriction (TAC)-induced cardiac hypertrophy. Further preliminary experiments showed that ATF4 protein expression was also significantly upregulated in the hypertrophic hearts. Besides, cardiomyocyte-specific deletion of Atf4 in mice inhibited compensatory cardiac hypertrophy and accelerated the progression of heart failure induced by TAC, and silencing of Atf4 in vitro inhibited phenylephrine-stimulated cardiomyocyte hypertrophy. Our transcriptome sequencing results showed that cardiomyocyte Atf4 knockout significantly inhibited the expression of Pfk2, whose product is a potent activator of PFK1, the rate-limiting enzyme in glycolysis. Meanwhile, seahorse assay showed that Atf4 knockdown significantly reduced the glycolytic capacity in cardiomyocytes. Furthermore, by bioinformatics analysis, we found ATF4 could bind with the promoter region of Pfk2. On this basis, we speculated that ATF4 might play a key role in the pathogenesis of cardiac hypertrophy by directly upregulating the expression of PFK2 and enhancing glycolytic capacity. By using cardiomyocyte-specific Atf4 knockout mice, transcriptome sequencing, non-targeted metabolomics, and ChIP etc, our project aims to firstly reveal the role and mechanism of cardiomyocyte ATF4 in the metabolic remodeling of cardiac hypertrophy, providing theoretical foundation for clinical translational research.