HINT1 (Histidine Triad Nucleotide-Binding Protein 1) Attenuates Cardiac Hypertrophy Via Suppressing HOXA5 (Homeobox A5) Expression

作者：Yan Zhang, Qiang Da, Siyi Cao, Ke Yan, Zhiguang Shi, Miao Qing, Chen Li, Lulu Hu, Shixiu Sun, Wei Wu, Lingxiang Wu, Feng Chen, Liansheng Wang, Yuanqing Gao, Zhengrong Huang, Yongfeng Shao, Hongshan Chen, Yongyue Wei, Feng Chen, Yi Han, Liping Xie, Yong Ji · 发表于：Circulation · 年份：2021 · DOI：10.1161/circulationaha.120.051094 · 被引用次数：64 · 研究领域：Congenital heart defects research、Developmental Biology and Gene Regulation、Genomics and Rare Diseases

Background: Cardiac hypertrophy is an important prepathology of, and will ultimately lead to, heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. This study aims to elucidate the effects and mechanisms of HINT1 (histidine triad nucleotide–binding protein 1) in cardiac hypertrophy and heart failure. Methods: HINT1 was downregulated in human hypertrophic heart samples compared with nonhypertrophic samples by mass spectrometry analysis. Hint1 knockout mice were challenged with transverse aortic constriction surgery. Cardiac-specific overexpression of HINT1 mice by intravenous injection of adeno-associated virus 9 (AAV9)–encoding Hint1 under the cTnT (cardiac troponin T) promoter were subjected to transverse aortic construction. Unbiased transcriptional analyses were used to identify the downstream targets of HINT1. AAV9 bearing shRNA against Hoxa5 (homeobox A5) was administrated to investigate whether the effects of HINT1 on cardiac hypertrophy were HOXA5-dependent. RNA sequencing analysis was performed to recapitulate possible changes in transcriptome profile.Coimmunoprecipitation assays and cellular fractionation analyses were conducted to examine the mechanism by which HINT1 regulates the expression of HOXA5. Results: The reduction of HINT1 expression was observed in the hearts of hypertrophic patients and pressure overloaded–induced hypertrophic mice, respectively. In Hint1 -deficient mice, cardiac hypertrophy deteriorat...