Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme for tryptophan metabolism, involved in immune cell differentiation/maturation and cancer biology. IDO1 is also expressed in cardiomyocytes, but its roles in the cardiovascular system are not fully understood. Here, we reported the functions of IDO1 during cardiac hypertrophy. Quantitative real-time PCR and Western blot experiments demonstrated the upregulation of IDO1 mRNA and protein levels in human and hypertrophic mouse hearts, as well as in angiotensin II (Ang II)-induced hypertrophic rat cardiomyocytes. IDO1 activity and metabolite product kynurenine were upregulated in rodent hypertrophic hearts and cardiomyocytes. Inhibition of IDO1 activity with PF-06840003 reduced Ang II-induced cardiac hypertrophy and rescued cardiac function in mice. siRNA-mediated knockdown of Ido1 repressed Ang II-induced growth in cardiomyocyte size and overexpression of hypertrophy-associated genes atrial natriuretic peptide (Anp or Nppa), brain natriuretic peptide (Bnp or Nppb), β-myosin heavy chain (β-Mhc or Myh7). By contrast, adenovirus-mediated rat Ido1 overexpression in cardiomyocytes promoted hypertrophic growth induced by Ang II. Mechanism analysis showed that IDO1 overexpression was associated with PI3K-AKT-mTOR signaling to activate the ribosomal protein S6 kinase 1 (S6K1), which promoted protein synthesis in Ang II-induced hypertrophy of rat cardiomyocytes. Finally, we provided evidence that inhibition of PI3K with pictilisib, AKT with perifosine, or mTOR with rapamycin, blocked the effects of IDO1 on protein synthesis and cardiomyocyte hypertrophy in Ang II-treated cells. Collectively, our findings identify that IDO1 promotes cardiomyocyte hypertrophy partially via PI3K-AKT-mTOR-S6K1 signaling.

吲哚胺 2,3-双加氧酶 1 (IDO1) 是一种色氨酸代谢酶，参与免疫细胞分化/成熟和癌症生物学。IDO1 也在心肌细胞中表达，但其在心血管系统中的作用尚不完全清楚。在这里，我们报告了 IDO1 在心脏肥大过程中的功能。定量实时 PCR 和蛋白质印迹实验证明了IDO1的上调人类和肥大小鼠心脏以及血管紧张素 II (Ang II) 诱导的肥大大鼠心肌细胞中的 mRNA 和蛋白质水平。IDO1 活性和代谢产物犬尿氨酸在啮齿动物肥大心脏和心肌细胞中上调。用 PF-06840003 抑制 IDO1 活性可减少 Ang II 诱导的小鼠心脏肥大并挽救小鼠的心脏功能。siRNA 介导的Ido1敲低抑制了 Ang II 诱导的心肌细胞大小增长和肥大相关基因心房利钠肽（Anp 或 Nppa）、脑利钠肽（Bnp 或 Nppb）、β-肌球蛋白重链（β-Mhc 或Myh7). 相比之下，腺病毒介导的大鼠Ido1在心肌细胞中的过表达促进了 Ang II 诱导的肥大性生长。机制分析表明，IDO1 过表达与 PI3K-AKT-mTOR 信号相关，可激活核糖体蛋白 S6 激酶 1 (S6K1)，从而促进 Ang II 诱导的大鼠心肌细胞肥大中的蛋白质合成。最后，我们提供的证据表明，用 pictilisib 抑制 PI3K，用哌立福新抑制 AKT，或用雷帕霉素抑制 mTOR，阻断了 IDO1 对 Ang II 处理细胞中蛋白质合成和心肌细胞肥大的影响。总的来说，我们的研究结果表明 IDO1 部分通过 PI3K-AKT-mTOR-S6K1 信号促进心肌细胞肥大。