The Center for Heart Development, State Key Laboratory of Development Biology of Freshwater Fish, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development College of Life Sciences, Hunan Normal University, Changsha, China.
Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China.
Am J Physiol Heart Circ Physiol. 2021 Apr 1;320(4):H1634-H1645. doi: 10.1152/ajpheart.00538.2020. Epub 2021 Feb 26.
Wnt/β-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may provide a tissue-specific clinical targeting strategy. encodes the core interaction factor of Wnt/β-catenin. Two homologs ( and ) have been identified in mammals. Different from the ubiquitous expression profile of , is enriched in cardiac tissue. However, the role of in mammalian cardiac disease is yet to be elucidated. In this study, we found that was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical β-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in -overexpressing transgenic (-TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, , , and c-Myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in -TG mice. Furthermore, in vivo downregulated during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway. In this study, we found that is associated with human pathological hypertrophy. Cardiac-specific overexpression of in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.
Wnt/β-catenin 信号通路在成人心血管病理性重构中发挥着关键作用。识别组织特异性的 Wnt/β-catenin 相互作用因子可能为组织特异性的临床靶向治疗策略提供依据。 编码 Wnt/β-catenin 的核心相互作用因子。哺乳动物中已经鉴定出两种 同源物（和）。与 的广泛表达模式不同，在心脏组织中丰富表达。然而，在哺乳动物心脏疾病中的作用尚未阐明。在这项研究中，我们发现 在伴有病理性肥大的人类心脏组织中上调。在小鼠心脏中特异性过表达 会自发导致心脏肥大，伴有心脏功能下降、心脏重量/体重和心脏重量/胫骨长度比值增加以及细胞尺寸增大。经典的 β-catenin/T 细胞转录因子 4（TCF4）复合物在过表达 的转基因（-TG）心脏组织中丰富，Wnt 信号的下游基因，即 、 、 和 c-Myc，上调。β-catenin 抑制剂的尾静脉注射有效挽救了 -TG 小鼠心力衰竭和病理性心肌重构的表型。此外，在心脏肥大状态下体内下调 拮抗激动剂诱导的心脏肥大。因此，本研究首次提供了体内证据，证明 以经典的 Wnt/β-catenin 依赖方式调节病理性心肌肥大，这可能为通过靶向该途径进行组织特异性临床治疗提供新的线索。在这项研究中，我们发现 与人类病理性肥大有关。在小鼠心脏中特异性过表达 会自发导致心脏肥大。同时，当在肥大模型小鼠中干扰 的表达时，心脏功能得到改善。本研究首次提供了体内证据，证明 以经典的 Wnt/β-catenin 依赖方式调节病理性心肌肥大，这可能为通过靶向该途径进行组织特异性临床治疗提供新的线索。
